microRNAs: Key players in virus‐associated hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is known as one of the major health problems worldwide. Pathological analysis indicated that a variety of risk factors including genetical (i.e., alteration of tumor suppressors and oncogenes) and environmental factors (i.e., viruses) are involved in beginning and development of HCC. The understanding of these risk factors could guide scientists and clinicians to design effective therapeutic options in HCC treatment. Various viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) via targeting several cellular and molecular pathways involved in HCC pathogenesis. Among various cellular and molecular targets, microRNAs (miRNAs) have appeared as key players in HCC progression. miRNAs are short noncoding RNAs which could play important roles as oncogenes or tumor suppressors in several malignancies such as HCC. Deregulation of many miRNAs (i.e., miR‐222, miR‐25, miR‐92a, miR‐1, let‐7f, and miR‐21) could be associated with different stages of HCC. Besides miRNAs, exosomes are other particles which are involved in HCC pathogenesis via targeting different cargos, such as DNAs, RNAs, miRNAs, and proteins. In this review, we summarize the current knowledge of the role of miRNAs and exosomes as important players in HCC pathogenesis. Moreover, we highlighted HCV‐ and HBV‐related miRNAs which led to HCC progression.

1. INTRODUCTION

Hepatocellular carcinoma (HCC) is found as the sixth common malignancy in the world (Gholamin et al., 2018; Yeh, Moles, & Nicot, 2016). It has been shown that a variety of risk factors including hepatitis C virus (HCV) infection, chronic hepatitis B virus (HBV), nonalcoholic fatty liver disease, and alcoholic cirrhosis are associated with initiation and progression of HCC (Moridikia, Mirzaei, Sahebkar, & Salimian, 2018). HCC is a type of cancer with poor prognosis because it has been diagnosed in advanced stages in many subjects. Several studies indicated that a variety of cellular and molecular signaling pathways are involved in HCC pathogenesis. Among several molecular mechanisms related to HCC pathogenesis, microRNAs (miRNAs) play a critical role in different stages of HCC. miRNAs are short noncoding RNAs which involved in the regulation of many cellular and molecular processes such as metastasis, growth, angiogenesis, and differentiation (Fathullahzadeh, Mirzaei, Honardoost, Sahebkar, & Salehi, 2016; Gholamin et al., 2018; Hesari et al., 2018; Keshavarz et al., 2018; Khani et al., 2018; Mirzaei, Gholamin, et al., 2016; Mirzaei, Sahebkar et al., 2016; Mirzaei, Fathullahzadeh, et al., 2018; Mirzaei, Masoudifar, et al., 2018; Mohammadi, Goodarzi, Jaafari, Mirzaei, & Mirzaei, 2016; Moridikia et al., 2018; Noruzi et al., 2018; Salarinia et al., 2016; Yeh et al., 2016). It has been shown that deregulation of miRNAs is associated with initiation and progression of various diseases, such as stroke, diabetes, cardiovascular diseases, and cancer (Banikazemi et al., 2018; Golabchi et al., 2018; Hoseini et al., 2018; Masoudi, Mehrabian, & Mirzaei, 2018; Mirzaei, 2017; Mirzaei, Momeni, et al., 2018; Mirzaei, Ferns, Avan, & Mobarhan, 2017; Noruzi et al., 2018; Rabieian et al., 2018; Rashidi, Hoseini, Sahebkar, & Mirzaei, 2017; Rashidi, Malekzadeh, Goodarzi, Masoudifar, & Mirzaei, 2017; Saeedi Borujeni et al., 2018). Hence, it seems that miRNAs could be used as prognostic, diagnostic, and therapeutic biomarkers for monitoring various diseases (Fathullahzadeh et al., 2016; Gholamin et al., 2016; Huan et al., 2013; Jafari et al., 2018; Jamali et al., 2018; Keshavarzi, Darijani, et al., 2017; Keshavarzi, Sorayayi, et al., 2017; Khanmohammadi, Mir, Baniebrahimi, & Mirzaei, 2018; Mashreghi et al., 2018; Mirzaei, Mirzaei, et al., 2018; Mirzaei, Sahebkar, Jaafari, Goodarzi, & Mirzaei, 2017; Saadatpour et al., 2016; Simonian, Mosallayi, & Mirzaei, 2018; Tavakolizadeh et al., 2018).

Increasing evidence indicated that miRNAs related to HBV and HCV infections via targeting various cellular and molecular signaling pathways could lead to the initiation and progression of HCC. Besides, deregulation of many miRNAs by infection viruses, other risk factors could also affect miRNAs profiles and lead to the development of HCC. Several studies have found that miRNAs act as oncogene and tumor suppressor and exert their effects with inducing and inhibition of vital biological processes related to HCC pathogenesis. These molecules are involved in cell proliferation, apoptosis, tumor growth, angiogenesis, and response to therapy. Hence, it seems that the identification of them could be associated with a better understanding of the roles of them in many signaling pathways. Moreover, several studies confirmed that miRNAs could be used as prognostic, diagnostic, and therapeutic biomarkers in HCC treatment. Besides miRNAs, exosomes as noncarriers have key roles for transferring pathogenesis messages to recipient cells. Exosomes are nano vehicles which could be released of a variety of cells such, as tumor cells, immune cells, and normal cells and via targeting their cargos (i.e., proteins, miRNAs, messenger RNAs, and DNAs) led to change the behavior of recipient cells. Hence, these nano vehicles could be used as attractive diagnostic and therapeutic biomarkers in HCC treatment. In the present review, we summarized various miRNAs as oncogene and tumor suppressor related to viral infections and other risk factors in HCC pathogenesis. Moreover, we highlighted exosomes as one of the important players in the initiation and progression of HCC.

2. mIRNAs AND HCC

Several studies have revealed an important role of miRNAs in HCC pathogenesis (Braconi, Henry, Kogure, Schmittgen, & Patel, 2011; Morishita & Masaki, 2015). miRNA enable to regulate a variety of targets involved in cancer via controlling a single gene (B. Zhang, Pan, Cobb, & Anderson, 2007) or through controlling multiple gene targets simultaneously (Damania et al., 2014; Y. Fang, Xue, Shen, Chen, & Tian, 2012; Fornari et al., 2010; Fu et al., 2017; Furuta et al., 2009; Garofalo et al., 2009; Y. Guo, Chen, Sun, & Yu, 2017; X. Jiang et al., 2012; F. F. Lan et al., 2011; W. Li, Dai, Ou, Zuo, & Liu, 2016; Y. Li et al., 2009, 2011; F. Lin et al., 2014; K. Liu et al., 2015; Shan et al., 2013; Shimizu et al., 2010; Shiu et al., 2017; K. Tu, Liu, Yao, Han, & Yang, 2016; L. Wang, Yao, et al., 2013; W. Wang, Zhang, et al., 2017; Wong et al., 2010; F. Xie et al., 2017; G. Xu et al., 2013; J. Xu, Zhu, et al., 2012; T. Xu et al., 2009; Y. Xu, Huang, et al., 2016; Yan, Chen, Li, Wang, & Fan, 2015; Yuan et al., 2012; B. Zhang et al., 2007; S. Zhang, Shan, et al., 2012; Y. Zhang, Wei, et al., 2012; Figure 1). miRNA networks are able to target one specific gene for fine‐tuning the expression of a specific protein in HCC cells (Buurman et al., 2012; Datta et al., 2008; S. Li et al., 2009; Shimizu et al., 2010; B. Zhang et al., 2007) or, alternatively, silencing a specific cellular and molecular pathway (W. Li et al., 2016; S. Tan, Li, Ding, Lobie, & Zhu, 2011; J. Xu et al., 2012; S. Zhang, Shan, et al., 2012).

Figure 1.

Various cellular and molecular mechanisms involved in HCC. HCC: hepatocellular carcinoma [Color figure can be viewed at wileyonlinelibrary.com]

The MTDH/PTEN/AKT pathway is one of the main pathways which disrupted in HCC. These pathways are associated with regulation of some miRNAs (Braconi et al., 2011). Several studies showed that miR‐145 was significantly decreased in HCC cell line and tissues, and miR‐145 decreased HDAC2, ROCK1, IRS1, and ADAM17 oncogene expression in HCC cells (W. Ding et al., 2016; Noh et al., 2013; Y. Wang, Hu, et al., 2014; X. Yang, Zhang, et al., 2014). PTEN is a mostly downregulated protein in HCC and is a part of a chemical pathway which is processing signals associated with cell proliferation. Also, it helps to control cell migration, cell adhesion to surrounding tissues, angiogenesis, and can play a function to preserve the stability of a cell genetic information (Leslie & Downes, 2004). It has been shown miR‐21, miR‐222, miR‐32, miR‐494, miR‐17‐5p, miR‐519a, miR‐519d, miR‐155‐5p, miR‐148a, miR‐30a‐5p, and miR‐93 via (Damania et al., 2014) regulating expression of PTEN and PTEN‐dependent pathways presented in vital cancerous processes, such as cell growth, migration, and invasion can contribute to HCC growth and spread (Burger et al., 2011; Damania et al., 2014; Fornari et al., 2012; Fu et al., 2017; K. Liu et al., 2015; F. Meng et al., 2007; Shan et al., 2013; K. Tu et al., 2016; Yan et al., 2015). In addition to, E2F3 is a cell cycle regulator and acts as an oncogene with the powerful proliferative role. It regulates several genes that play an important role in signal transduction, transcription, and DNA synthesis. It has been showed that the regulation of E2F3 is associated with cancer progression. The results of some studies showed that it likely involved in various processes during cancer such as DNA damage, apoptosis, cell‐to‐cell connection, cell proliferation, and epithelial–mesenchymal transition in HCC (X. Zeng et al., 2014). miR‐141, miR‐195, miR‐503, miR‐217, and miR‐144 are miRNAs that are potentially involved in inhibition of HCC progression though targeting E2F3 HCC cell line and tissues (T. Cao, Li, Hu, Ma, & Cai, 2014; J. Su, Wang, Liu, & Zhong, 2014; Xiao, Zhang, Chen, et al., 2013; T. Xu et al., 2009; J. Xue et al., 2014). The proto‐oncogene c‐Myc is overexpressed in a large number of human tumors and overexpression of c‐Myc in hepatic cells leads to the development of HCC. c‐Myc during hepatocarcinogenesis interact with some target genes and has also effective roles in regulating of growth, apoptosis, and differentiation (C.‐P. Lin, Liu, Lee, Chan, & Liu, 2010). Some studies have shown that miR‐744, Let‐7g, miR‐ 320a by targeting c‐Myc could lead to the suppression of HCC cell growth (F. F. Lan et al., 2011; F. Lin et al., 2014; F. Xie et al., 2017). miR‐29 is another miRNA which has an important role in hepatocarcinogenesis via regulation of various targets involved in apoptosis such as Bcl‐2 and Mcl‐1 proteins (Xiong et al., 2010). T. Xu et al. (2009) reported that miR‐195 upregulation can inhibit G1/S transition in HCC cells. They indicated that it could suppress tumorigenicity and HCC cell proliferation by suppressing Rb‐E2F signaling via affecting on cyclin D1, CDK6, and E2F3. Moreover, upregulation of miR‐195 led to regulating cell proliferation, induced G1 phase cell cycle arrest, and induction of cell death though targeting Wnt3a. These findings indicated that miR‐195 could act as a tumor suppressor in HCC (Y. Yang, Li, et al., 2014). In addition to, miR‐21 is involved in regulation of the PTEN gene, and is also associated with several biological pathways in HCC cells. Some studies have proposed that miR‐21 is involved in enhancing cell proliferation, invasion, migration, apoptosis, and cell elongation in HCC cells (Bao et al., 2013; E. C. Connolly, Van Doorslaer, Rogler, & Rogler, 2010; C. Liu et al., 2010; F. Meng et al., 2007; G. Xu et al., 2013). In summary, miRNAs have several roles in cancer progression and development, acting as either tumor suppressors or oncogenes under certain conditions—also key suppressors or activators of tumor metastasis (Golabchi et al., 2017). Some factors, such as alteration of miRNAs expression and their target effectors can cause the effect on the cell phenotype and disease susceptibility (Mirzaei, Gholamin, et al., 2016). It also suggested that deregulation of miRNAs via activation or inhibition, in which a sequence of cellular and molecular mechanisms, such as maintaining proliferative signaling, induction of tumor cells apoptosis, activating metastasis, and invasion could be involved in cancer progression (Jafari et al., 2017). As a result, recognition of the pattern of deregulated miRNA expression in HCC provides precious information to recognize new biomarkers for human cancer recognition, disease prognosis, and monitoring of response to therapy (Mirzaei, 2017). However, to further identify the molecular mechanisms controlling miRNA and cancer processes more studies in preclinical models and patients are required.

3. mIRNA AS PROGNOSTIC AND DIAGNOSTIC BIOMARKERS IN HCC

The relationship between miRNAs expression patterns and development and transformation of tumor cells, such as HCC, has been shown in several studies (Assal, Tayebi, Hosny, Esmat, & Abdelaziz, 2015; B. Wang et al., 2010). Many miRNAs have been recognized from clinical and preclinical studies, as shown in Table 1, which could be associated with HCC progression. Yau et al. (2013) reported that miR‐106b were upregulated in the patient with HCC. Yau et al. (2013) indicated that the level of miR‐106b in HCC tumor tissue was significantly higher in patients with HCC compared with nontumor tissue. Moreover, the high level of miR‐106b was remarkably associated with higher tumor grade. Z. Su, Zhao, et al. (2014) showed that the level of miR‐25 was significantly overexpressed in HCC tissue. In the referred study, expression of miR‐25 was significantly correlated with tumor node metastasis (TNM) stage. Furthermore, studies have shown that the expression of miR‐17‐5p and miR‐222 from serum samples and the expression of miR‐191, miR‐183, miR‐372, and miR‐221 from tissue samples were significantly upregulated and associated with TNM stage of HCC (Y. W. Dang, Chen, Liao, & Wang, 2013; H. Gu, Guo, Zou, Zhu, & Zhang, 2013; Z. Liang et al., 2013; M. X. Zhan et al., 2013; J. Zheng, Dong, Gao, Wang, & Yu, [Link]). H. Su et al. (2009) screened 308 miRNAs in 39 HCC patients and normal hepatic tissue using microarray method. The results demonstrated that expression of 29 miRNAs was different in HCC tissues and revealed that miR‐101 was altered in the HCC tissues and cell line, compared with normal hepatic tissue. Moreover, Y. Zhang, Guo, et al. (2012) suggested that the reduced the expression of miR‐101 in clinical HCC tissues associated with tumor aggressiveness. Furthermore, the expression level of miR‐200a, miR‐210, and miR‐125b have correlated with total survival of HCC patients (W. Li et al., 2008; Xiao, Zhang, Zhou, et al., 2013; M. Zhan et al., 2014). Some studies have confirmed that downregulation of various miRNAs including miR‐101, miR‐214, and miR‐148b in clinical HCC tissue is associated with vein invasion of HCC (J. Wang, Li, Wang, Zheng, & Ma, 2013; Y. Zhang, Guo, et al., 2012; Z. Zhang, Zheng, & Hai, 2014). J. Wang, Li, et al. (2012) studies indicated that the miR‐182 can promote metastasis of HCC and upregulation of it were associated with intrahepatic metastasis. L. Chen, Jiang, Yuan, and Tang (2012) suggested that the level of miR‐17‐5p in HCC with metastasis higher than HCC without metastasis. While after surgery for predicting distant metastasis and local relapse can be used from miR‐221 deregulation used in HCC tissues (Yoon et al., 2011). These findings suggest that some miRNAs can be considered as new prognostic markers or tumor progression monitoring.

Table 1.

microRNA and HCC

microRNAs	Expression	Target	Tumor suppressor/oncogenesis	Model	Sample size	References
miR‐21	Up	PTEN	Oncogenic	HCC tumor tissues Cell line		F. Meng et al. (2007)
miR‐21	Up	PTEN hSulf‐1	Oncogenic	Cell line Mice		Bao et al. (2013)
miR‐21	Up	PTEN PDCD4 RECK	Oncogenic	HCC tissue samples Cell line	20	C. Liu et al. (2010)
miR‐21	Up	PDCD4	Oncogenic	HCC tissue samples Mice Cell line	33	X. Qiu et al. (2013)
miR‐17–92 Polycistron and miR‐21	Up	E2F1	Oncogenic	HCC tissue samples Cell line	19	E. Connolly et al. (2008)
miR‐21	Up	PDCD4 Phosphatase PTEN	Oncogenic	Cell line		Damania et al. (2014)
miR‐21	Up	MAP2K3	Oncogenic	HCC tissue samples Cell line	14	G. Xu et al. (2013)
miR‐21	Up	RHOB	Oncogenic	Cell line		E. C. Connolly et al. (2010)
miR‐21	Up		Oncogenic	HCC tissue samples Cell line	19	E. Connolly et al. (2008)
miR‐32	Up	PTEN	Oncogenic	HCC tissue samples Cell line	36	Yan et al. (2015)
miR‐494	Up	PTEN	Oncogenic	HCC tissue samples Cell line	44	K. Liu et al. (2015)
miR‐221	Up	p27 DDIT4	Oncogenic	HCC tissue samples Mice Cell line	104	Pineau et al. (2010)
miR‐221	Up	CDKN1B/p27 CDKN1C/p57	Oncogenic	HCC tissue samples Cell line	39	Fornari et al. (2008)
miR‐221	Up	Bmf	Oncogenic	HCC tissue samples Cell line	51	Gramantieri et al. (2009)
miR‐18a	Up	ESR1	Oncogenic	HCC tissue samples Cell line	80	W. H. Liu et al. (2009)
miR‐224	Up	API‐5	Oncogenic	HCC tissue samples Cell line	19	Y. Wang et al. (2008)
miR‐224	Up	PPP2R1B	Oncogenic	HCC tissue samples Cell line	47	D. Ma, Tao, Gao, Fan, and Wu (2012)
miR‐224	Up	HOXD10	Oncogenic	HCC tissue samples Cell line		Q. Li et al. (2014)
miR‐200a	Up		Oncogenic	HCC tissue samples Mice Cell line	105	Murakami et al. (2011)
miR‐200b	Up	SMURF2	Oncogenic	HCC tissue samples Mice Cell line	105	Murakami et al. (2011)
miR‐200b	Down	BMI1	Suppressor	HCC tissue samples Mice Cell line	42	W. R. Wu, Sun, et al. (2016)
miR‐106b‐25 cluster	Up	E2F1	Oncogenic	HCC tissue samples Cell line	56	Y. Li et al. (2009)
miR‐106b‐25 cluster	Up	BH3‐only protein Bim E2F1	Oncogenic	HCC tissue samples Cell line	56	Bai et al. (2009)
miR‐25	Up	Bim	Oncogenic	HCC tissue samples Cell line	56	Y. Li et al. (2009)
miR‐106b	Up		Oncogenic	HCC tissue samples Cell line	120	Yen, Su, Lee, Liu, and Yen (2016)
miR‐106b	Up	EMT	Oncogenic	HCC tissue samples Mice Cell line	99	Yau et al. (2013)
miR‐106b	Up	APC Cyclin D1	Oncogenic	HCC tissue samples Cell line	8	G. Shen, Jia, Tai, Li, and Chen (2012)
miR‐17–92 cluster	Up		Oncogenic	HCC tissue samples Cell line	56	Y. Li et al. (2009)
miR‐17–92	Up	E2F1	Oncogenic	HCC tissue samples Cell line	19	E. Connolly et al. (2008)
miR‐17–92	Up		Oncogenic	HCC tissue samples Cell line	19	E. Connolly et al. (2008)
miR‐17–5p	Up	NA	Oncogenic	HCC tissue samples Mice Cell line	25	F. Yang, Yin, et al. (2010)
miR‐17–5p	Up	PTEN	Oncogenic	Mice Cell line		Shan et al. (2013)
miR‐17–3p	Up	GalNT7 vimentin	Oncogenic	Mice Cell line		Shan et al. (2013)
miR‐92b	Up	Smad7	Oncogenic	HCC tissue samples Mice Cell line	31	Zhuang et al. (2016)
miR‐331–3p	Up	ING5	Oncogenic	HCC tissue samples Mice Cell line		Y. Cao et al. (2015)
miR‐331–3p	Up	PHLPP	Oncogenic	HCC tissue samples Mice Cell line	120	R. M. Chang, Yang, Fang, Xu, and Yang (2014)
miR‐143	Up	FNDC3B	Oncogenic	HCC tissue samples Cell line	13	X. Zhang et al. (2009)
miR‐9	Up	KLF17	Oncogene‐like miRNA	Mice Cell line		Z. Sun et al. (2013)
miR‐519a	Up	PTEN/PI3K/AKT signaling	Oncogenic	HCC tissue samples Cell line	116	K. Tu et al. (2016)
miR‐519d	Down	MKi67	Suppressor	Cell line		Y.‐Y. Hou et al. (2011)
miR‐519d	Up	CDKN1A/p21 PTEN AKT3 TIMP2	Oncogenic	HCC tissue samples Cell line	56	Fornari et al. (2012)
miR‐130b	Up	TP53INP1	Oncogenic	HCC tissue samples Mice Cell line	35	S. Ma et al. (2010)
miR‐130b	Up	PPAR‐γ	Oncogenic	HCC tissue samples Cell line	86	K. Tu et al. (2014)
miR‐155	Up	SOX6	Oncogenic	HCC tissue samples Mice Cell line	30	Q. Xie et al. (2012)
miR‐155	Up	Wnt signaling	Oncogenic	HCC tissue samples Mice Cell line	10	Y. Zhang, Wei, et al. (2012)
miR‐155	Up	ARID2	Oncogenic	HCC tissue samples Mice Cell line	124	L. Zhang, Wang, et al. (2016)
miR‐155–5p	Up	PTEN	Oncogenic	HCC tissue samples Mice Cell line	28	Fu et al. (2017)
miR‐ 155–3p	Up	FBXW7	Oncogenic	HCC tissue samples Mice Cell line	45	B. Tang et al. (2016)
miR‐191	Up	SOX4 IL1A TMC7	Oncogenic	HCC tissue samples Cell line	30	Elyakim et al. (2010)
miR‐216a	Up	TSLC1	Oncogenic	HCC tissue samples	48	P. J. Chen et al. (2012)
miR‐216a/217 cluster	Up	PTEN SMAD7	Oncogenic	HCC tissue samples Mice Cell line	21	H. Xia, Ooi, and Hui (2013)
miR‐222	Up	PTEN	Oncogenic	HCC tissue samples Mice Cell line	72	Garofalo et al. (2009)
miR‐222	Up	p27	Oncogenic	HCC tissue samples Cell line	5	le Sage et al. (2007)
miR‐222	Up	AKT signaling (PPP2R2A)	Oncogenic	HCC tissue samples Cell line	99	Wong et al. (2010)
miR‐373	Up	PPP6C	Oncogenic	HCC tissue samples Cell line	26	N. Wu, Liu, et al. (2011)
miR‐423	Up	45Cip1/Waf1	Oncogenic	Cell line		J. Lin et al. (2011)
miR‐517a	Up	NA	Oncogenic	HCC tissue samples Mice Cell line	165	Toffanin et al. (2011)
miR‐151	Up	RhoGDIA	Oncogenic	HCC tissue samples Mice Cell line	23	J. Ding et al. (2010)
miR‐181b	Up	TIMP3	Oncogenic	Mice Cell line		B. Wang et al. (2010)
miR‐210	Up	VMP1	Oncogenic	HCC tissue samples Mice Cell line	48	Ying et al. (2011)
miR‐183	Up	PDCD4	Oncogenic	HCC tissue samples Cell line	25	J. Li et al. (2010)
miR‐183/96/182	Up	FOXO1	Oncogenic	HCC tissue samples Cell line	81	Leung, He, Chan, Law, and Wong (2015)
miR‐602	Up	RASSF1A	Oncogenic	HCC tissue samples Cell line	21	L. Yang, Ma, et al. (2010)
miR‐141	Up	DLC‐1	Oncogenic	Cell line		Banaudha et al. (2011)
miR‐141	down	E2F3	Suppressor	HCC tissue samples Cell line	20	J. Xue et al. (2014)
miR‐490–3p	Up	ERGIC3	Oncogenic	HCC tissue samples Cell line	20	L. Zhang, Liu, Li, and Tang (2013)
miR‐590–5p	Up	TGF‐β RII	Oncogenic	Cell line		X. Jiang et al. (2012)
miR‐148a	Up	PTEN	Oncogenic	HCC tissue samples Mice Cell line	19	Yuan et al. (2012)
miR‐10b	Up	CADM1	Oncogenic	HCC tissue samples Cell line	34	Q. Li et al. (2012)
miR‐96	Up		Oncogenic	Cell line		R.‐X. Chen, Xia, Xue, and Ye (2012)
miR‐27a	Up		Oncogenic	HCC tissue samples Cell line	24	X.‐J. Wu et al. (2013)
miR‐657	Up	TLE1	Oncogenic	HCC tissue samples Mice Cell line	28	L. Zhang, Yang, et al. (2013)
miR‐301a	Up	Gax	Oncogenic	HCC tissue samples Cell line	25	P. Zhou et al. (2012)
miR‐454	Up	CHD5	Oncogenic	HCC tissue samples Mice Cell line	40	L. Yu, Gong, et al. (2015)
miR‐500a	Up	SFRP2 GSK‐3β	Oncogenic	HCC tissue samples Cell line	17	Y. Guo et al. (2017)
miR‐543	Up	PAQR3	Oncogenic	HCC tissue samples Cell line	60	L. Yu, Zhou, et al. (2014)
miR‐135a	Up	FOXO1	Oncogenic	Cell line		Y.‐B. Zeng et al. (2016)
miR‐33a	Up	PPARα	Oncogenic	HCC tissue samples Cell line	86	W. Chang, Zhang, Xian, and Yu (2017)
miR‐184	Up	INPPL1	Oncogenic	HCC tissue samples Cell line	21	B. Gao, Gao, Li, Huang, and Lin (2014)
miR‐184	Up	SOX7	Oncogenic	HCC tissue samples Cell line	8	G. G. Wu, Li, et al. (2014)
miR‐330	Up	ING4	Oncogenic	HCC tissue samples Mice Cell line	78	X. Hu, Feng, Sun, Qu, and Sun (2017)
miR‐4262	Up	PDCD4	Oncogenic	HCC tissue samples Cell line	18	S. Lu et al. (2016)
miR‐24	Up	SOX7	Oncogenic	HCC tissue samples Cell line	26	Y. Ma, She, Ming, and Wan (2014)
miR‐362–5p	Up	CYLD	Oncogenic	HCC tissue samples Mice Cell line	36	Wingo et al. (2015)
miR‐93	Up	PTEN CDKN1A	Oncogenic	HCC tissue samples Cell line	47	Ohta et al. (2015)
miR‐153	Up	WWOX	Oncogenic	HCC tissue samples Mice Cell line	42	Hua, Jiang, Huang, Liao, and Ding (2015)
miR‐452	Up	SOX7	Oncogenic	HCC tissue samples Mice Cell line	180	Z. Zheng et al. (2016)
miR‐452	Up	CDKN1B	Oncogenic	HCC tissue samples Cell line	35	Z. Zheng et al. (2016)
miR‐103	Up	AKAP12	Oncogenic	HCC tissue samples Mice Cell line	12	W. Xia et al. (2016)
miR‐192–5p	Up	SEMA3A	Oncogenic	Mice Cell line		Yan‐Chun et al. (2017)
miR‐29	Down	Collagen	Suppressor	Serum Murine	67	Roderburg et al. (2011)
miR‐29	Down	Bcl‐2 Mlc‐1	Suppressor	HCC tissue samples Mice Cell line	127	Xiong et al. (2010)
miR‐29c	Down	SIRT1	Suppressor			Bae et al. (2014)
miR‐29c	Down	VEGFA	Suppressor	HCC tissue samples Cell line	87	L. Liu et al. (2017)
miR‐29c	Down	SIRT1	Suppressor	HCC tissue samples Cell line	50	Bae et al. (2014)
miR‐29a	Down	PPM1D	Suppressor	Cell line		X. Z. Meng et al. (2011)
miR‐199a	Down	HIF‐1a	Suppressor	HCC tissue samples Mice Cell line		X. Q. Jia et al. (2012)
miR‐199a/b‐3p	Down	PAK4	Suppressor	HCC tissue samples Cell line		J. Hou et al. (2011)
miR‐199a‐3p	Down	mTOR c‐MET	Suppressor	HCC tissue samples Cell line	39	Fornari et al. (2010)
miR‐199a‐3p	Down	VEGFA VEGFR1 VEGFR2 HGF MMP‐2	Suppressor	HCC tissue samples Mice Cell line	6	Ghosh et al. (2017)
miR‐199a‐5p	Down	DDR1	Suppressor	HCC tissue samples Cell line	23	Q. Shen et al. (2010)
miR‐199a‐5p and let‐7c	Down	MAP4K3	Suppressor	HCC tissue samples Cell line	45	J. Tang et al. (2017)
miR‐19b	Down	TGFβRII	Suppressor	HCC tissue samples rat	21	Lakner et al. (2012)
miR‐145	Down	CUL5	Suppressor	HCC tissue samples Cell line	25	F. Gao, Sun, Wang, Tang, and Yan (2015)
miR‐145	Down	HDAC2	Suppressor	HCC tissue samples Mice Cell line	13	Noh et al. (2013)
miR‐145	Down	ROCK1	Suppressor	HCC tissue samples Cell line	96	W. Ding et al. (2016)
miR‐145	Down	IRS1	Suppressor	HCC tissue samples Cell line	48	Y. Wang, Hu, et al. (2014)
miR‐145	Down	ADAM17	Suppressor	HCC tissue samples Cell line	48	X. Yang, Zhang, et al. (2014)
miR‐30d	Up	GNAI2	Oncogenic	HCC tissue samples Mice Cell line	23	Yao et al. (2010)
miR‐30a	Down	SNAI1	Suppressor	HCC tissue samples Cell line	63	Z. Liu, Tu, and Liu (2014)
miR‐ 30a‐5p	down	MTDH/PTEN/AKT pathway	Suppressor	HCC tissue samples Cell line	16	W. Li et al. (2016)
miR‐375	Down	AEG‐1	Suppressor	HCC tissue samples Cell line	60	N. Xu et al. (2012)
miR‐375	Down	YAP	Suppressor	HCC tissue samples Cell line	48	A. M. Liu, Poon, and Luk (2010)
miR‐375	Down	ATG7	Suppressor	HCC tissue samples Mice Cell line	20	Y. Chang et al. (2012)
miR‐22	down	HDAC4	Suppressor	HCC tissue samples Cell line	160	J. Zhang, Yang, et al. (2010)
miR‐22	down	Galectin‐1	Suppressor	HCC tissue samples Cell line	26	You et al. (2016)
miR‐22	down	YWHAZ	Suppressor	HCC tissue samples Cell line	372	M. Chen et al. (2016)
miR‐520e	Down	ERK1/2 and NF‐kB signaling	Suppressor	HCC tissue samples Cell line	23	S. Zhang, Shan, et al. (2012)
miR‐520g	Up	SMAD7	Oncogenic	HCC tissue samples Cell line	130	Kan, Guo, Huang, and Liu (2015)
miR‐138	Down	CCND3	Suppressor	HCC tissue samples Mice Cell line	18	W. Wang, Zhao, Tan, Ren, and Qi (2012)
miR‐138	Down	TERT	Suppressor	HCC tissue samples Cell line	5	Shiu et al. (2017)
miR‐1	Down	FOXP1 c‐MET HDAC4	Suppressor	Cell line		Datta et al. (2008)
miR‐122	Down	Bcl‐w	Suppressor	Cell line		C. Lin, Gong, Tseng, Wang, and Wu (2008)
miR‐122	Down	ADAM7	Suppressor	HCC tissue samples Mice Cell line	48	Tsai et al. (2009)
miR‐122	Down	ADAM1 SRF Igf1R	Suppressor	HCC tissue samples Mice Cell line		Y. Xu et al. (2016)
miR‐122	Down	Wnt/b‐catenin signaling pathways	Suppressor	HCC tissue samples Cell line	30	J. Xu et al. (2012)
miR‐122	Down	Tfdp2 E2f1	Suppressor	Mice Cell line		B. Wang, Hsu, et al. (2014)
miR‐101	down	Mcl‐1	Suppressor	HCC tissue samples Cell line	39	Su et al. (2009)
miR‐101	Down	FOS	Suppressor	HCC tissue samples Cell line	20	S. Li et al. (2009)
miR‐101	Down	DNMT3A	Suppressor	HCC tissue samples Cell line	32	X. Wei et al. (2013)
miR‐101	Down	SOX9	Suppressor	HCC tissue samples Cell line	130	Y. Zhang, Guo, et al. (2012)
miR‐101	Down	VEGF‐C	Suppressor	HCC tissue samples Cell line	20	Z. Liu, Wang, Mao, Zou, and Fan (2016)
miR‐101	Down	NLK	Suppressor	HCC tissue samples Cell line	10	Q. Shen et al. (2014)
miR‐101	Down	EZH2	Suppressor	HCC tissue samples Mice Cell line	12	L. Xu et al. (2014)
miR‐195	Down	cyclin D1 CDK6 E2F3	Suppressor	HCC tissue samples Cell line		T. Xu et al. (2009)
miR‐195	Down	LATS2	Suppressor	Cell line		X. Yang, Yu, et al. (2012)
miR‐195	Down	Bcl‐w	Suppressor	Cell line		X. Yang, Yin, et al. (2012)
miR‐195	Down	Wnt3a	Suppressor	HCC tissue samples Cell line	28	Y. Yang, Li, et al. (2014)
miR‐195	Down	CBX4	Suppressor	HCC tissue samples Mice Cell line	10	C. Zheng et al. (2015)
miR‐497–195 Cluster	Down	CCNE1 CDC25A CCND3 CDK4 BTRC	Suppressor	HCC tissue samples Mice Cell line	18	Furuta et al. (2013)
miR‐23b	Up/down dysregulate	uPA c‐met	Suppressor	HCC tissue samples Cell line	17	Salvi et al. (2009)
miR‐23b	Down	Pyk2	Suppressor	HCC tissue samples Cell line	50	J. Cao et al. (2017)
miR‐205	Down	HBx mRNA (HBV protein)	Suppressor	HCC tissue samples Mice Cell line	33	T. Zhang, Zhang, et al. (2013)
miR‐9	Down	IGF2BP1	Suppressor	HCC tissue samples Cell line	85	J. Zhang, Cheng, et al. (2015)
miR‐615–5p		insulin‐like growth factor‐II (IGF‐II)	Suppressor	HCC tissue samples Cell line	20	El Tayebi, Hosny, Esmat, Breuhahn, and Abdelaziz (2012)
Let‐7g	down	c‐Myc p16	Suppressor	Cell line		F. F. Lan et al. (2011)
let‐7g	Down	COL1A2	Suppressor	HCC tissue samples Cell line	55	J. Ji et al. (2010)
hsa‐let‐7g	Down	c‐Myc p16INK4A	Suppressor	Cell line		F. F. Lan et al. (2011)
Let‐7c	Down	Bcl‐xL	Suppressor	HCC tissue samples Cell line		Shimizu et al. (2010)
Let‐7g	Down	Bcl‐xL	Suppressor	HCC tissue samples Cell line		Shimizu et al. (2010)
miR‐7	Down	PIK3CD mTOR p70S6K	Suppressor	Mice Cell line		Y. Fang et al. (2012)
miR‐7	Down	CCNE1	Suppressor	Cell line		Zhang et al. (2014)
miR‐26a	Down	Cyclin D2 Cyclin E2	Suppressor	Mice Cell line		Kota et al. (2009)
miR‐26a	Down	IL‐6‐Stat3 signaling	Suppressor	HCC tissue samples Mice Cell line	130	X. Yang, Liang, et al. (2013)
miR‐26a	Down	EZH2	Suppressor	HCC tissue samples Mice Cell line	67	D.‐N. Ma et al. (2016)
miR‐26a	Down	HGF	Suppressor	HCC tissue samples Mice Cell line	120	X. Yang, Zhang, et al. (2014)
miR‐26b‐5p	Down		Suppressor	HCC tissue samples Mice Cell line	41	Y. Wang, Sun, et al. (2016)
miR‐34a	Down	MACF1 LMNA GFAP ALDH2	suppressor	Cell line		Cheng et al. (2010)
miR‐34a	Down	c‐MET	Suppressor	HCC tissue samples Cell line	83	Y. Dang, Luo, Rong, and Chen (2013)
miR‐34a	Down	HDAC1	Suppressor	HCC tissue samples Cell line	60	T.‐Y. Sun et al. (2017)
miR‐34a	Down	Bcl‐2	Suppressor	HCC tissue samples Cell line	30	F. Yang, Li, et al. (2014)
miR‐99a	Down	IGF‐1R mTOR	Suppressor	HCC tissue samples Cell line	142	D. Li et al. (2011)
miR‐99a	Down	AGO2	Suppressor	HCC tissue samples Mice Cell line	111	J. Zhang, Jin, et al. (2014)
miR‐124	Down	CDK6	Suppressor	HCC tissue samples Cell line	19	Furuta et al. (2009)
miR‐124	Down	ROCK2 EZH2	Suppressor	HCC tissue samples Mice Cell line	131	F. Zheng et al. (2012)
miR‐124	Down	PIK3CA	Suppressor	Mice Cell line		Lang and Ling (2012)
miR‐124	Down	STAT3	Suppressor	HCC tissue samples Cell line		Y. Lu, Yue, Cui, Zhang, and Wang (2013)
miR‐185	NA	Six1	Suppressor	HCC tissue samples Cell line		Imam et al. (2010)
miR‐185	Up	Six2	Suppressor	Cell line		S. M. Zhu, Chen, et al. (2016)
miR‐193b	Down	Cyclin D1 ETS1	Suppressor	HCC tissue samples Cell line	25	C. Xu et al. (2010)
miR‐219–5p	Down	GPC3	Suppressor	HCC tissue samples Cell line	83	N. Huang et al. (2012)
miR‐223	Down	STMN1	Suppressor	HCC tissue samples Cell line	42	Wong et al. (2008)
miR‐449	Down	c‐MET	Suppressor	HCC tissue samples Mice Cell line	23	Buurman et al. (2012)
miR‐637	Down	LIF	Suppressor	HCC tissue samples Mice Cell line	52	J. Zhang, He, et al. (2011)
miR‐125b	Down	LIN28B2	Suppressor	HCC tissue samples Cell line		L. Liang et al. (2010)
miR‐125b	Down	PIGF MMP‐2 MMP‐9	Suppressor	HCC tissue samples Cell line	19	Alpini et al. (2011)
miR‐125b	Down	Mcl‐1 IL6R	Suppressor	HCC tissue samples Cell line	32	H.‐Y. Jia et al. (2012)
miR‐125b	Down	TAZ	Suppressor	HCC tissue samples Cell line	20	J. Li, Fang, Yu, and Wang (2015)
miR‐125a	Down	MMP11 VEGF	Suppressor	HCC tissue samples Mice Cell line	80	Bi et al. (2012)
miR‐139	Down	ROCK2	Suppressor	HCC tissue samples Mice Cell line	63	Bi et al. (2012)
miR‐139	Down	TCF‐4	Suppressor	HCC tissue samples Mice Cell line	50	W. Gu, Li, and Wang (2014)
miR‐142–3p	Down	RAC1	Suppressor	Cell line		L. Wu, Cai, et al. (2011)
miR‐142–3p	Down	RAC1	Suppressor	HCC tissue samples Cell line	11	L. Wu, Cai, et al. (2011)
miR‐181a	Down	OPN	Suppressor	Cell line		S. D. Bhattacharya et al. (2010)
miR‐ 15a‐5p	Down	BDNF	Suppressor	HCC tissue samples Mice Cell line	13	Long, Jiang, Liu, Fang, and Kuang (2016)
miR‐15a	Down	HBx transcript (HBV protein)	Suppressor	Cell line		Y. Wang, Jiang, et al. (2013)
miR‐15b	Down	Bcl‐w	Suppressor	HCC tissue samples Cell line	25	Chung et al. (2010)
miR‐503	Down	Cyclin D3 E2F3	Suppressor	HCC tissue samples Mice Cell line	125	Xiao, Zhang, Chen, et al. (2013)
miR‐503	Down	PRMT1	Suppressor	HCC tissue samples Cell line	20	B. Li, Liu, Li, and Wu (2015)
miR‐20a	Down	Mcl‐1	Suppressor	HCC tissue samples Cell line	100	Fan et al. (2013)
miR‐100	Down	plk1	Suppressor	HCC tissue samples Cell line	15+134	P. Chen, Zhao, and Ma (2013)
miR‐152	Down	DNMT1	Suppressor	HCC tissue samples Mice Cell line	20	J. Huang, Wang, Guo, and Sun (2010)
miR‐16–1	Down	Transcript (HBV protein)	Suppressor	Cell line		Y. Wang, Jiang, et al. (2013)
miR‐214	Down	XBP‐1	Suppressor	HCC tissue samples Mice Cell line	23	Duan et al. (2012)
miR‐214	Down	HDGF	Suppressor	HCC tissue samples Mice Cell line	68	Shih et al. (2012)
miR‐214	Down	β‐Catenin	Suppressor	HCC tissue samples Mice Cell line		X. Wang, Chen, et al. (2012)
miR‐148b	Down	ROCK1	Suppressor	Cell line		X. Chen, Bo, Lu, Zhou, and Chen (2016)
miR‐148b	Down	WNT1	Suppressor	HCC tissue samples Mice Cell line	40	J. G. Zhang, Shi, et al. (2015)
miR‐1271	Down	GPC3	Suppressor	HCC tissue samples Cell line	112	Maurel et al. (2013)
miR‐140	Down	Dnmt1	Suppressor	HCC tissue samples Mice Cell line	10	Takata et al. (2013)
miR‐ 140–5p	Down	TGFBR1 FGF9	Suppressor	HCC tissue samples Mice Cell line	120	H. Yang, Fang, Chang, and Yang (2013)
miR‐140–5p	Down	CTHRC1	Suppressor	HCC tissue samples Cell line	30	C. Y. Wang, Zhang, et al. (2016)
miR‐198		HGF/c‐MET pathway	Suppressor	Cell line		S. Tan et al. (2011)
miR‐302b	Down	EGFR/AKT2/CCND1 pathway	Suppressor	HCC tissue samples Cell line	27	L. Wang, Yao, et al. (2013)
miR‐217	Down	E2F3	Suppressor	HCC tissue samples Cell line	21	J. Su et al. (2014)
miR‐146a	Down	HAb18G	Suppressor	HCC tissue samples Mice Cell line	53	Z. Zhang, Zhang, Sun, Ma, and Chen (2015)
miR‐126–3p	Down	LRP6 PIK3R2	Suppressor	HCC tissue samples Mice Cell line	70	Du et al. (2014)
miR‐126	Down	SOX2	Suppressor	Cell line		C. Zhao, Li, Zhang, Yang, and Chang (2015)
miR‐9–3p		TAZ (WWTR1)	Suppressor	HCC tissue samples Cell line		Higashi et al. (2015)
miR‐144	down	E2F3	Suppressor	HCC tissue samples Cell line	33	T. Cao et al. (2014)
miR‐188–5p	down	FGF5	Suppressor	HCC tissue samples Mice Cell line	192	F. Fang et al. (2015)
miR‐ 486–5pA	Down	PIK3R1	Suppressor	HCC tissue samples Mice Cell line	72	X. P. Huang et al. (2015)
miR‐ 338–3p	Down	FOXP4	Suppressor	HCC tissue samples Cell line	30	G. Wang, Sun, et al. (2015)
miR‐424	Down	c‐Myb	Suppressor	HCC tissue samples Cell line	80	L. Yu, Ding, et al. (2014)
miR‐377	Down	TIAM1	Suppressor	HCC tissue samples Cell line	50	G. Chen, Lu, Liu, Shan, and Yuan (2015)
miR‐1285–3p	Down	JUN	Suppressor	HCC tissue samples Cell line	97	J. Liu et al. (2015)
miR‐744	Down	c‐Myc	Suppressor	HCC tissue samples Cell line	40	F. Lin et al. (2014)
miR‐335	Down	ROCK1	Suppressor	HCC tissue samples Cell line	62	H. Liu, Li, Chen, Pei, and Long (2015)
miR‐451	Down	ATF2	Suppressor	HCC tissue samples Cell line	26	Lv et al. (2014)
miR‐129–5p	Down	PDK4	Suppressor	HCC tissue samples Mice Cell line	88	Han et al. (2016)
miR‐129–2	Down	HMGB1	Suppressor	HCC tissue samples Mice Cell line	106	Z. Liu et al. (2016)
miR‐186	Down	YAP1	Suppressor	Cell line		Ruan, He, Yu, and Hang (2016)
miR‐592	Down	IGF‐1R	Suppressor	HCC tissue samples Cell line	42	W. Wang, Zhang, et al. (2017)
miR‐211	Down	SATB2	Suppressor	HCC tissue samples Mice Cell line	20	G. Jiang et al. (2015)
miR‐211	Down	SPARC	Suppressor	HCC tissue samples Mice Cell line	227	Deng et al. (2016)
miR‐98	Down	SALL4	Suppressor	HCC tissue samples Mice Cell line	144	W. Zhou et al. (2016)
miR‐874–3p	Down	PIN1	Suppressor	HCC tissue samples Mice Cell line	50	Leong et al. (2017)
miR‐105–1	Down	NCOA1	Suppressor	HCC tissue samples Cell line		Y.‐S. Ma et al. (2017)
miR‐1246		NFIB	Suppressor	HCC tissue samples Cell line		Q. Zhang, Cao, et al. (2015)
miR‐1246	Up	CADM1	Suppressor	HCC tissue samples Cell line	38	Z. Sun et al. (2014)
miR‐212	Down	FOXA1	Suppressor	HCC tissue samples Cell line	86	H. Tu et al. (2015)
miR‐ 320a	Down	c‐Myc	Suppressor	HCC tissue samples Cell line	50	F. Xie et al. (2017)
miR‐133b	Down	Sirt1	Suppressor	HCC tissue samples Mice Cell line	37	Z. Tian et al. (2016)
miR‐133a	Down	IGF‐1R	Suppressor	HCC Tissue samples Mice Cell line	40	W. Zhang, Liu, et al. (2015)
miR‐608	Down	MIF	Suppressor	HCC Tissue samples Cell line	42	K. Wang, Liang, Wei, Zhang, and Zhu (2016)
miR‐613	Down	DCLK1	Suppressor	HCC Tissue samples Mice Cell line	38	W. Wang, Zhang, Wang, Zhang, and Tang (2016)
miR‐770		FBXW7	Suppressor	Cell line		W.‐J. Wu, Shi, et al. (2016)
miR‐149	Down	AKT1	Suppressor	HCC Tissue samples Cell line	130	Y. Zhang, Guo, et al. (2014)
miR‐363	Down	S1PR1	Suppressor	Cell line		P. Zhou, Huang, et al. (2014)
miR‐625	Down	IGF2BP1	Suppressor	HCC Tissue samples Mice Cell line	99	X. Zhou et al. (2015)
miR‐127	Down	Sept7	Suppressor	HCC Tissue samples Mice Cell line	33	J. Zhou, Lu, et al. (2014)

Note. HCC: hepatocellular carcinoma.

4. miRNAs AS THERAPEUTIC TARGETS IN HCC

Many studies have shown that the changes in expression level of miRNAs was associated with several diseases (J. Hayes, Peruzzi, & Lawler, 2014). As many miRNAs are overexpressed in HCC, targeting this group by employing antisense oligonucleotides may present a new therapeutic approach. Okada et al. (2015) studied the impact of locked nucleic acid (LNA)‐anti‐miR‐214 in a hepatic fibrosis mouse model. They observed that LNA‐anti‐miR‐214 remarkably decreased the fibrotic state or inflammation of the liver and tumor number and volume. Also, in vitro, LNA‐anti‐miR‐214 significantly improved transforming growth factor‐β1‐induced profibrotic gene expression. Consistently, Wagenaar et al. (2015) reported that treatment liver cancer cell line with anti‐miR‐21 leads to robust induction of cell death and necrosis. In addition, destruction of miR‐21 activity resulted in the prevention of HCC tumor cell migration and the block of tumor growth. Also, inhibition of miR‐21 contributed to the sensitivity of HCC cells to IFN‐a/5‐FU (Tomimaru et al., 2010). In addition, X. Huang et al. (2017) indicated that the suppression of miR‐17 family by anti‐miR‐17 family oligonucleotide led to inhibit HCC growth in a SCID/Beige mice model. It has been shown that miR‐22 has the antiproliferative effect on HCC cells through regulation of HDAC4, offering miR‐22 is potential as a tumor suppressor. Moreover, this miRNA with the targeting of YWHAZ/AKT/FOXO3a signaling and inhibition oncogene galectin‐1 display tumor‐suppressive effects in HCC cells (M. Chen et al., 2016; You et al., 2016; J. Zhang, Yang, et al., 2010). Moreover, Ou, Zhai, Wu, and Li (2015) illustrated that miR‐363 targets Mcl‐1 in cisplatin resistance of HCC cell, whereas miR‐363 upregulation can sensitize HCC cells to cisplatin. K. Liu et al. (2015) confirmed that miR‐494 which suppresses the translation of the PTEN and induce expression of PI3K and p‐13K caused the promotion of cell viability, invasion, migration, and reduced the cell apoptosis and sensitivity of HCC cells to sorafenib. Furthermore, has been reported that downregulation of c‐FLIP via miR‐512‐3p caused Taxol‐induced apoptosis in HCC cells (F. Chen et al., 2010). Lee et al. (2017) illustrated that the overexpression of miR‐200a‐3p lead to the increase of anticancer drug resistance in HCC cells through downregulation DUSP6 expression. These reports suggested that deregulation of miRNAs could change the expression of oncogenic potential or tumor suppressing of their targets and finally cause to therapeutic effects. Thus, identification of novel miRNAs as attractive therapeutic candidates opens a new window in the treatment of HCC (Table 2).

Table 2.

MicroRNA and response to therapy

microRNAs	Expression in HCC	Target gene	Drug	Sample (patient/cell line)	References
miR‐122	Down		Sorafenib	Cell line	Bai et al. (2009)
miR‐122	down	IGF‐1R	Sorafenib	Cell line	Y. Xu et al. (2016)
miR‐122			5‐fluorouracil	Cell line	J. Yin et al. (2011)
miR‐122	Down	PKM2	Doxorubicin	Cell line	Pan et al. (2016)
miR‐21		PTEN PDCD4	Interferon (IFN)‐α/5‐fluorouracil (5‐FU)	Cell line	Tomimaru et al. (2010)
miR‐512–3p	Up	c‐FLIP	Taxol	Cell line	F. Chen et al. (2010)
miR‐199a‐3p		mTOR c‐Met	Doxorubicin	Cell line	Fornari et al. (2010)
miR‐199a‐5p	Down		Cisplatin	Cell line	N. Xu et al. (2012)
miR‐1274a	Up	ADAM9	Sorafenib	Cell line	C. Zhou, Liu, et al. (2011)
miR‐195		BCL‐w	5‐Fluorouracil	Cell line	X. Yang, Yin, et al. (2012)
miR‐193a		uPA	Sorafenib	Patient (n=39) Cell line	Salvi et al. (2013)
miR‐199a	Up		Propofol	Cell line	J. Zhang, Wu, Zhang, Feng, and Zhu (2013)
miR‐193a‐3p		SRSF2	5‐Fluorouracil	Cell line	Lakner et al. (2012)
miR‐182	Up	TP53INP1	Cisplatin	Patient (n=33) Cell line	Qin, Luo, Qian, and Chen (2014)
miR‐363	Down	Mcl‐1	Cisplatin	Patient (n=30) Cell line	Ou et al. (2015)
miR‐222			Sorafenib	Cell line	K. Liu et al. (2014)
miR‐34a		Bcl‐2	Sorafenib	Cell line	F. Yang, Li, et al. (2014)
miR‐125b	Down	hexokinase II	5‐Fluorouracil	Cell line	J.‐X. Jiang, Gao, Pan, Yu, and Sun (2014)
miR‐491		SMAD3	Arsenic trioxide	Cell line	F. Jiang et al. (2014)
miR‐193b		Mcl‐1	Sorafenib	Cell line	Mao et al. (2014)
miR‐193b		Mcl‐1	Cisplatin	Cell line	W. Yin, Nie, Zhang, Xie, and He (2015)
miR‐26b		TAK1 TAB3	Doxorubicin	Cell line	N. Zhao et al. (2014)
miR‐494	Up	PTEN	Sorafenib	Patient Cell line	K. Liu et al. (2015)
miR‐21	Down		5‐Fluorouracil pirarubicin	Patient (n=67) Cell line	X. He et al. (2015)
miR‐21	Down	PTEN	Sorafenib	Cell line	C. He et al. (2015)
miR‐877	Up	FOXM1	Paclitaxel	Cell line	X. Huang, Qin, and Lu (2015)
miR‐425–3p	Up		Sorafenib	Patient (n=26) Cell line	Vaira et al. (2015)
miR‐367–3p		MDM2	Sorafenib	Patient Cell line	J. Xu et al. (2016)
miR‐539			Arsenic trioxide	Cell line	C. Zhu, Zhou, Zhou, Chang, and Jiang (2016)
miR‐125a	Up		Sorafenib	Cell line	Potenza et al. (2017)
miR‐200a‐3p		DUSP6	5‐Fluorouracil	Cell line	Lee et al. (2017)
miR‐205–5p	Up	PTEN/JNK/ANXA3 pathway	5‐Fluorouracil	Cell line	Shao et al. (2017)
miR‐137	Down	ANT2	Sorafenib	Cell line	A.‐Q. Lu, Lv, Qiu, Wang, and Cao (2017)
miR‐101		Mcl‐1	Doxorubicin	Cell line	H. He, Tian, Chen, & Deng (2016)
let‐7c	Up	Bcl‐xL	Sorafenib	Cell line	Shimizu et al. (2010)
miR‐17–92 cluster		EGFR IL‐6 signaling pathway	Sorafenib	Cell line	Awan et al. (2017)
miR‐33a‐5p	Down		Cisplatin	Cell line	W. Meng et al. (2017)
miR‐29a	Up	TET–SOCS1–MMP‐9 signaling axis	5‐Hydroxymethylcytosine	Cell line Patient(n= 431)	Q. Chen et al. (2017)
miR‐9	Down	eIF‐5A‐2	Cetuximab	Cell line	F. Xue et al. (2018)
miR‐7	Up	TYRO3	Sorafenib	Cell line	Kabir et al. (2017)
miR‐16	Up		Pien Tze Huang (PZH)	Cell line	Qi et al. (2017)
miR‐200a/b	Up		Curcumin	Cell line	H.‐H. Liang et al. (2013)
miR‐503	Up	EIF4E	5‐Fluorouracil	Cell line	X. Yang et al. (2017)
miR‐221	Up	caspase‐3	Sorafenib	Cell line Patient	Fornari et al. (2017)

Note. HCC: hepatocellular carcinoma.

5. miRNAs RELATED WITH HBV

One of the most common human pathogens is the HBV that often lead to chronic hepatitis, liver cirrhosis, and HCC (Di Bisceglie, 2009). Chronic HBV infection is the main etiological factor for HCC and the risk of HCC progression in individuals with chronic HBV infections 100‐fold more than uninfected individuals (Song, Kim, & Choo, 2013). Many reports have indicated that the aberrant activity of several signaling pathways involved in cell differentiation, proliferation, and angiogenesis is contributed to the development of HCC (Tomimaru et al., 2010). Unfortunately, the precise molecular mechanisms engaged in the development of HBV‐related HCC remain incompletely unclear (Lamontagne, Steel, & Bouchard, 2015). It has been known that miRNAs have significant function in the regulation of cellular homeostasis and with its function as tumor suppressor genes or oncogenes dependent on the function of the target genes could contribute to the development or inhibition of the progression of many cancers such as HBV‐associated hepatocarcinogenesis (Table 3; Lamontagne et al., 2015; McCaffrey, 2009). Kohno et al. (2014) showed that in HBV‐transfected HepG2 cells, miR‐1231 was upregulated and due to which the expression of HBV core protein is reduced HBV replication is suppressed. Moreover, miR‐210, miR‐125a‐5p, and miR‐199a‐3p suppress the HBV replication via targeting and reduction of S gene expression (Potenza et al., 2011; G. Zhang, Li, et al., 2010). H. Guo et al. (2011) showed that miR‐372/373 was significantly upregulated in HepG2.2.15 cells and it improved the expression levels of HBx (HBV protein X) and HBV core protein. Also, they reported that miR‐372/373 through inhibition of the host transcription factor nuclear factor I/B (NFIB) lead to the increase of HBV replication (H. Guo et al., 2011). Protein HBXIP host by interaction with HBx, which could lead to inhibition of its function. Jin et al. (2013) suggested that miR‐501 upregulated in HCC samples and in HBV‐infected cell lines and enhance HBV replication via targeting of HBXIP (Jin et al., 2013). X. Zhang, Zhang, et al. (2011) showed that upregulation of miR‐1 level in hepatoma cell promoted HBV replication via inhibiting histone deacetylase 4 (HDAC4) and increased the expression of farnesoid X receptor (FXRA). FXRA interacts with RXRA and so FXRA/RXRA complex binds to core promoter of HBV genome to elevate its activity. Also, acetylation of H3/H4 histones by HDACs lead to binding to the HBV genome and regulates the replication and transcription of HBV (X. Zhang, Zhang, et al., 2011). miR‐122 is one of the miRNAs that is strongly expressed in the liver of HCC patients and significantly correlated with HBV infection. L. Qiu et al. (2010) indicated that miR‐122 enhanced HBV replication by targeting heme oxygenase 1. In contrast, another study showed that miR‐122 could suppress HBV replication (F. Ji et al., 2011). These reports showed that interaction between miRNAs and risk factors involved in HCC such as HBV play a critical role in the development of HCC.

Table 3.

HBV–HCC microRNAs

microRNAs	Expression	Model	Sample size	Method	Target	Function	References
hsa‐miR‐190b_R+1	Up	Human	261	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis	Y. Tan et al. (2014)
hsa‐miR‐141–3p	Up	Human	261	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis	Y. Tan et al. (2014)
hsa‐miR‐4532_R+2	Up	Human	261	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis	Y. Tan et al. (2014)
hsa‐mir‐6127‐p3	Up	Human	261	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis	Y. Tan et al. (2014)
hsa‐miR‐99b‐3p_R22	Up	Human	261	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis	Y. Tan et al. (2014)
hsa‐miR‐30a‐3p	Down	Human	261	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis	Y. Tan et al. (2014)
hsa‐miR‐199a‐5p	Down	Human	261	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis	Y. Tan et al. (2014)
hsa‐let‐7 f‐5p	Down	Human	261	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis/elevation in ALT > 40 (U/L)	Hung et al. (2016); Y. Tan et al. (2014)
hsa‐miR‐192–5p	Down	Human	261	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis	Y. Tan et al. (2014)
hsa‐miR‐98–5p	Down	Human	261	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis	Y. Tan et al. (2014)
hsa‐miR‐574–3p	Down	Human	261	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis	Y. Tan et al. (2014)
hsa‐miR‐30e‐3p	Down	Human	261	Deep sequencing and qRT‐PCR	Autophagy‐related genes (ATG5 and ATG12)/homeobox A1	Differentiation of HCC and cirrhosis	S. Bhattacharya et al. (2016); Y. Tan et al. (2014)
miR‐206	Up	Human	260	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis/biomarker	Y. Tan et al. (2014)
miR‐26a‐5p	Down	Human	260	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis/biomarker	Y. Tan et al. (2014)
miR‐433–3p	Up	Human	260	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis/biomarker	Y. Tan et al. (2014)
miR‐1228–5p	Up	Human	260	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis/biomarker	Y. Tan et al. (2014)
miR‐199a‐5p	Down	Human	260	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis/biomarker	Y. Tan et al. (2014)
miR‐192–5p	Down	Human	260	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis	Y. Tan et al. (2014)
miR‐192	Up	Human	112	Microarray and qRT‐PCR	p53‐responsive tumor suppressor	Differentiation of HCC and chronic hepatitis B	Motawi, Shaker, El‐Maraghy, and Senousy (2015); J. Zhou, Yu, et al. (2011)
miR‐21	Up	Human		Microarray and qRT‐PCR		Differentiation of HCC and chronic hepatitis B	J. Zhou, Yu, et al. (2011)
miR‐223	Down	Human		Microarray and qRT‐PCR		Differentiation of HCC and chronic hepatitis B	J. Zhou, Yu, et al. (2011)
miR‐26a	Down	Human		Microarray and qRT‐PCR		Differentiation of HCC and chronic hepatitis B/biomarker	J. Zhou, Yu, et al. (2011)
miR‐27a	Down	Human		Microarray and qRT‐PCR		Differentiation of HCC and chronic hepatitis B	J. Zhou, Yu, et al. (2011)
miR‐801	Up	Human		Microarray and qRT‐PCR		Differentiation of HCC and chronic hepatitis B	J. Zhou, Yu, et al. (2011)
miR‐16	Down	Human	120	Microarray and qRT‐PCR	CDKN1A (p21)	Differentiation of HCC and chronic hepatitis B/prognosis	Yen et al. (2016); J. Zhou, Yu, et al. (2011)
miR‐100	Up	Human	23	miScript miRNA PCR Array		Differentiation of HCC	Y. Wang, Gao, et al. (2015)
miR‐200a	Down	Human	23	miScript miRNA PCR Array		Differentiation of HCC	Y. Wang, Gao, et al. (2015)
miR‐222	Down	Human	23	miScript miRNA PCR Array		Differentiation of HCC	Y. Wang, Gao, et al. (2015)
miR‐145	Up	Human	23	miScript miRNA PCR Array		Differentiation of HCC	Y. Wang, Gao, et al. (2015)
miR‐375	Up	Human		qRT‐PCR	Glucose homeostasis	Differentiate HCC/hepatocarcinogenesis	Afonso, Rodrigues, Simão, and Castro (2016); L. Li et al. (2010)
hsa‐miR‐6852–5p	Down	Human	261	Deep sequencing and qRT‐PCR		Differentiation of HCC and cirrhosis	Y. Tan et al. (2014)
miR‐92a‐3p	Up	Human	20	qRT‐PCR		Noninvasive biomarker for HCC	Giray et al. (2014)
MiR‐141	Down	Human	261	qRT‐PCR	PPARα	decreases transcription of the HBV/diagnostic/differentiate HCC	C. Hayes and Chayama (2016); Y. Tan et al. (2014)
miR‐125b‐5p	Up	Human	20	qRT‐PCR		Noninvasive biomarker for HCC	Giray et al. (2014)
miR‐223–3p	Down	Human	20/23	qRT‐PCR/miScript miRNA PCR Array		Noninvasive biomarker for HCC/Differentiation of HCC	Giray et al. (2014) Y. Wang, Gao, et al. (2015)
miR‐150	Down	Human	120	qRT‐PCR	Inhibit CD133‐positive liver cancer stem cells by targeting c‐Myb	Diagnosis and prognosis/tumor suppressor	F. Yu, Lu, Chen, Dong, and Zheng (2015)
miR‐126	Up	Human	59	Microarry/qRT‐PCR		Diagnostic biomarker	Ghosh et al. (2016)
miR‐142–3p	Up	Human	59	Microarry/qRT‐PCR		Diagnostic biomarker for HBV–HCC	Ghosh et al. (2016)
miR‐19a	Down	Human	112	qRT‐PCR	PTEN, SOX4 APAF1, Beclin1, and PAK6	Biomarkers/diagnostic	Motawi et al. (2015)
miR‐195	Down	Human	112	qRT‐PCR	Targeting FGF7 and GHR	Biomarkers for HBV‐associated HCC/ regulating the G1/S transition in HCC/ with high diagnostic accuracy for HCC	Motawi et al. (2015)
miR‐22	Down			qRT‐PCR	Regulating (CDKN1A), (CDK6), (SIRT1), and (Sp1)	Tumor suppressor/diagnostic	C. Hayes and Chayama (2016); H.‐T. Zhu et al. (2012)
miR‐29a	Down	Human	120			Prognostic biomarker	Cho et al. (2017)
miR‐26a	Down	Human	120			Prognostic biomarker	Cho et al. (2017)
miR‐216b	Down	Human/in vitro	150	RT‐PCR	3′‐UTR of insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2)	Prognostic/suppresses cell proliferation	F. Y. Liu et al. (2016)
miR‐7	Up	In vitro			3′‐UTR of maspin	Poor prognosis in HCC	W.‐S. Chen et al. (2015)
miR‐107	Up	In vitro			3′‐UTR of maspin	Poor prognosis in HCC	W.‐S. Chen et al. (2015)
miR‐99a	Down	In vitro			Nuclear factor‐κB	Inflammation and tumorigenesis/prognosis	C. Hayes and Chayama (2016); D. Li et al. (2011)
miR‐219–5p	Down	Human / in vitro	83	qRT‐PCR	Glypican‐3 (GPC3)	Inhibit proliferation	N. Huang et al. (2012)
miR‐181a	Up	In vitro		qRT‐PCR/microarray	PTEN 3′‐UTR	Therapeutic	Y. Tian et al. (2017)
miR‐15b	Down	50 patients in vitro	50	Microarray analysis/RT‐PCR	Fucosyl transferase 2	Suppressed tumor growth / therapeutic/elevation in ALT > 40 (U/L)	Hung et al. (2016); C. S. Wu, Yen, et al. (2014)
miR‐145	Down	Human	25	RT‐PCR	The 3′‐UTR of CUL5 and RAB5C	Inhibiting oncogenes/therapeutic	F. Gao et al. (2015)
miR‐34c	Down	Human		RT‐PCR	Transforming growth factor‐β‐induced factor homeobox 2 (TGIF2)	Inhibited cell proliferation and induced apoptosis/diagnostic and therapeutic	Y. Wang, Wang, et al. (2015)
miR‐29c	Down	Human/in vitro			TNFAIP3	Suppresses HBV DNA replication/ diagnostic and therapeutic	C.‐M. Wang et al. (2011)
miR‐125a	Down	In vitro		RT‐PCR	Inhibits translation of the S transcript	Suppressed HBV replication/therapeutics	C. Hayes and Chayama (2016); Potenza et al. (2011)
miR‐224	Up	HCC tissue in vitro		In Situ Hybridization (miRNA ISH)/ Fluorescent miRNA ISH/miRNA ISH‐Electron Microscopy	Smad4	Migration/tumor formation/therapeutic	S. H. Lan et al. (2014)
miR‐181a	Up	In vitro		qRT‐PCR	mRNA 3′UTR of transcription factor E2F5 / TNF receptor superfamily member 6 (Fas)	Promoted cell growth and tumor formation/downregulate Fas expression and suppress apoptosis	Hesari et al. (2018); Zou et al. (2015, 2014)
miR‐101–3p	Down	In vitro		qRT‐PCR	3′‐UTR of Rab5a	Suppression of proliferation and migration	Sheng et al. (2014)
miR‐18a	Up	Human		qRT‐PCR		Proliferation and reduced the level of estrogen receptor‐α	Sohn et al. (2015)
miR‐221	Up	Human	120	qRT‐PCR		Dysregulating DNA damage‐inducible transcript 4/Bmf gene and apoptosis in HCC/elevation in ALT > 40 (U/L)	Hung et al. (2016); Sohn et al. (2015)
miR‐222	Up	Human		qRT‐PCR		Migration in HCC through with AKT signaling	Sohn et al. (2015)
miR‐224	Up	Human		qRT‐PCR		Differentiation HCC and LC	Sohn et al. (2015)
miR‐106b‐25	Up	Human	38	qRT‐PCR	Prevent excessively high E2F1 expression	Oncogenic potential/regulation of c‐myc and E2F1	Y. Li et al. (2009); Sohn et al. (2015)
miR‐17–92	Up	Human	38	qRT‐PCR		Oncogenic potential/egulation of c‐myc and E2F1	Y. Li et al. (2009)
miR‐195	Down	Human		RT‐PCR		Suppressed tumorigenicity/regulated the G1/S transition of HCC cells	Sohn et al. (2015)
miR‐15a	Down	Human/in vitro	40	RT‐PCR	Transforming growth factor β (TGF‐β) pathway‐inhibitory factor Smad7	Affect apoptosis (Bcl‐2 pathway)	Shi, Xin, Chai, Liu, and Ma (2015)
miR‐155	Up	In vitro		RT‐PCR/microarray	C/EBP	Promotes cell growth	B. Wang et al. (2009)
miR‐501	Down	Human	50	RT‐PCR	HBXIP	Decreases transcription of the HBV	H. Guo et al. (2011); C. Hayes and Chayama (2016)
miR‐548p	Down	Human/in vitro		qRT‐PCR	HBXIP	/tumor suppressor/inhibited cell growth, proliferation and promoting cell apoptosis	X. M. Hu et al. (2016)
miR‐449a	Down	In vitro		RT‐PCR/microarray analysis	cAMP‐responsive element binding protein 5 (CREB5)	Inhibited proliferation	X. Zhang, Liu, et al. (2016)
miR‐210	Up	In vitro		RT‐PCR and western blot	Inhibited the pre‐S1 region	Suppressed HBV replication	C. Hayes and Chayama (2016); G. Zhang, Li, et al. (2010)
miR‐21	NA	In vitro/in vitro	120 / 23	qRT‐PCR	PDCD4, PTEN, HEPN1, HBx, and 3′‐UTR of maspin	Upregulation by HBx/activation of STAT3/prognosis/inhibit HEPN1/ carcinogenesis/most miRNA in cancer/biomarker	INVALID CITATION; Amr et al. (2016); Cho et al. (2017); Ghosh et al. (2016); Hung et al. (2016)
miR‐122–5p	NA	Human/in vitro	120 / 260	Deep sequencing and qRT‐PCR	Hnf4α/GALNT10 3′ UTR of the core protein	Biomarker/Differentiation/prognostic/elevation in ALT > 40 (U/L)	Cho et al. (2015); Ghosh et al. (2016); Y. Tan et al. (2014); Q. Wu et al. (2015)
miR‐101	Down	Human		RT‐qPCR		Induced apoptosis in HCC	Sohn et al. (2015)

Note. 3′‐UTR: 3′‐untranslated region; ALT: alanine transaminase; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; mRNA: messenger RNA; qRT‐PCR: quantitative real‐time polymerase chain reaction.

6. miRNA RELATED WITH HCV

HCV infection commonly induces chronic liver inflammation and epidemiologic evidence exactly proved that persistent infection with HCV is a significant risk factor for the development of HCC (Andrade et al., 2009). As mentioned above, miRNAs have shown essential roles in the several biological pathways involved in HCC and profound effect on the HCV replication and transcription (H. Li, Jiang, & Peng, 2016). Varnholt et al. (2008) screened 80 miRNAs in 52 HCV‐infected human primary liver tumors by a quantitative real‐time polymerase chain reaction panel. The results revealed 19 downregulated and 10 upregulated miRNAs compared with the normal liver samples. Also, miR‐122, miR‐100, miR‐10a, miR‐198, and miR‐145 were further tested in 43 HCC samples and nine dysplastic nodules. In hepatic tumors, miR‐145 and miR‐198 were significantly downregulated whereas miR‐10a, miR‐100, and miR‐122 were overexpressed in hepatic tumors compared with the control group (Varnholt et al., 2008). Y. Zhang, Wei, et al. (2012) reported significantly overexpression of miR‐155 levels in patients who infected with HCV and upregulation of miR‐155 induced tumorigenesis and proliferation of hepatocyte via activating Wnt signaling. Oksuz et al. (2015), screened the expression of 58 miRNA in 64 patient's plasma HCV‐positive HCC, HCV‐positive cirrhosis, and chronic hepatitis C. The results revealed that miR‐302c‐3p, miR‐223‐3p, miR‐17‐5p, and miR‐30c‐5p were observed remarkably deregulated for cirrhosis and HCC and could be used as new noninvasive markers in detection of HCV‐positive HCC at early stage and cirrhosis stage. Morita et al. (2011) assessed the expression of the miR‐122 level and HCV load in the 185 liver samples from patients infected with HCV. They concluded that no correlation with HCV load and miR‐122 expression in the human liver and level of miR‐122 expression was an inverse relationship with the intensity of functional and histopathological liver damage. Chowdhury et al. (2012) reported that miR‐130a significantly overexpressed in the liver biopsy and HCV‐infected hepatocytes samples and they indicated that this miRNA by targeting of IFITM1 could inhibit IFN‐I signaling pathway and induce HCV replication. Y. Chen et al. (2013) illustrated that miR‐21 was overexpressed in human Huh 7 cell infected with HCV and helps in evasion of HCV from the host immune system with the targeting of the MyD88 and IRAK1 that lead to negatively regulating HCV‐induced IFN‐I signaling (Y. Chen et al., 2013). In the cell culture, upregulation of miR‐29 causes to reduce HCV replication and miR‐29 was downregulated in most of the patient with HCV infection (Bandyopadhyay et al., 2011). Furthermore, it was observed that miR‐29 via targeting COL1A1, COL3A1 maybe play a role in the hepatic stellate cell and promote inflammation (Bandyopadhyay et al., 2011; Shrivastava, Mukherjee, & Ray, 2013). These reports showed that deregulation of miRNAs could regulate the HCV replication and cell biological pathway (Table 4). Therefore, identification of new miRNAs as therapeutic biomarkers open a new window in the treatment of HCC.

Table 4.

HCV–HCC microRNAs

microRNAs	Expression	Model	Sample	Method	Target	Function	References
miR‐483–5p	Up	human		qRT‐PCR	SRF, MAPK3	Indicators of liver damage by HCV	Shwetha et al. (2013)
miR‐30c‐5p	Up	Human	8	qRT‐PCR		Noninvasive biomarker for HCV related HCC	El‐abd, Fawzy, El‐sheikh, and Soliman (2015) Oksuz et al. (2015)
miR‐223–3p	Down	Human	28	qRT‐PCR	insulin‐like growth Factor 1 receptor	Noninvasive biomarker for HCV related HCC	S. Bhattacharya et al. (2016); El‐abd et al. (2015); Oksuz et al. (2015)
miR‐302c‐3p	Up	Human	8	qRT‐PCR		Noninvasive biomarker for HCV related HCC	El‐abd et al. (2015); Oksuz et al. (2015)
miR‐17–5p	Up	Human	8	qRT‐PCR		Noninvasive biomarker for HCV related HCC	El‐abd et al. (2015); Oksuz et al. (2015)
miR‐618	Up	Human	32	RT‐PCR	LPR12	Detection and progression of HCC	Abdalla and Haj‐Ahmad (2012); H. Li et al. (2016)
Mir‐650	Down	Human	32	RT‐PCR	TRAF4	Detection and progression of HCC	Abdalla and Haj‐Ahmad (2012); H. Li et al. (2016)
miR‐126	Down	Human	23	RT‐PCR		Diagnostic marker inhibit tumorigenesis and metastasis	Khairy, Hamza, Shaker, and Yosry (2016)
miR‐129	Down	Human	23	RT‐PCR		Diagnostic marker	Khairy et al. (2016)
miR‐885–5p		Human	192	qRT‐PCR		Detection of HCC	Zekri et al. (2016)
miR‐29b		Human	192	qRT‐ PCR		Detection of HCC	Zekri et al. (2016)
miR‐221		Human	192	qRT‐PCR		Detection of HCC	Zekri et al. (2016)
miR‐375	Up	human		qRT‐PCR	glucose homeostasis	Differentiate HCC/hepatocarcinogenesis	Afonso et al. (2016); L.‐M. Li et al. (2010)
miR‐21	Up	Human	137	qRT‐PCR		Diagnosis of HCC/differentiate HCC	J. Zhou, Yu, et al. (2011)
miR‐141	Up	In vitro		qPCR	DLC‐1	Enhanced HCV replication/differentiate HCC/diagnostic	Banaudha et al. (2011); Singaravelu, Russell, Tyrrell, and Pezacki (2014)
miR‐130a	Up	Human	112	qRT‐PCR	Mitotic cell cycle, protein modification process, and cell differentiation	Differentiate HCC from CLD and fibrosis/diagnostic	Motawi et al. (2015)
miR‐34a	Up	Human	112	qRT‐PCR	PDGFRA, E2F5, Foxp1, c‐Met, Wnt1, and Notch1	Defines HCC treatment strategies diagnostic	Motawi et al. (2015)
miR‐146a	Up	Human	112	qRT‐PCR	Regulator of toll‐like receptor signaling and NF‐κB via TRAF6 and IRAK1	Negative effects on antitumor immune response/diagnostic/therapeutic	Bandiera et al. (2016); Motawi et al. (2015)
miR‐195	Down	Human	112	qRT‐PCR	targeting FGF7 and GHR	Biomarkers for HCC/regulating the G1/S transition in HCC/ diagnostic and therapeutic	Motawi et al. (2015)
miR‐192	Up	Human	112	qRT‐PCR	p53‐responsive tumor suppressor/TGFβ1	Biomarkers for HCC/diagnostic	Afonso et al. (2016); Motawi et al. (2015); Wen et al. (2015)
miR‐296	Up	Human	112	qRT‐PCR	VEGF receptors	Regulating (VEGF) receptors and tumor angiogenesis/carcinogenesis and dysregulating p53/diagnostic for HCC	Motawi et al. (2015)
miR‐30e	Down	Human	28		autophagy‐related genes (ATG5 and ATG12) / homeobox A1	Detection	S. Bhattacharya et al. (2016)
miR‐494	Up	Human	224	qRT‐PCR		Progress of liver fibrosis to HCC	Elemeery, Badr, Mohamed, and Ghareeb (2017)
miR‐1269	Up	Human	224	qRT‐PCR		Progress of liver fibrosis to HCC	Elemeery et al. (2017)
miR‐16	Down	Human	90	qRT‐PCR		Biomarker and indicators of the progress of HCC	Ge et al. (2014); El‐abd et al. (2015)
miR‐199a/b‐3p	Down	In vitro / Human	40	RT‐PCR	PAK4, c‐Met, mTOR	Suppress HCC/diagnostic, prognostic and therapeutic	El‐abd et al. (2015); W. Hou, Tian, Zheng, and Bonkovsky (2010); H. Li et al. (2016)
miR‐203a	Down	In vitro		qRT‐PCR	EMT	Inhibited EMT and tumor growth / poor prognosis of HCC	D. Liu et al. (2015)
miR‐155	Up	Human	10	qRT‐PCR	APC	Promote HCC/prognostic and therapeutic	H. Li et al. (2016); Y. Zhang, Wei, et al. (2012)
miR‐143	Up	Human	95	qRT‐PCR	FNDC3B	Cancer cell invasion, migration and tumor metastasis by repression of FNDC3B/biomarker for the hepatitis and HCC	X. Zhang et al. (2009); Z. Zhang, Meng, et al. (2014)
miR‐215	Up	Human	95	qRT‐PCR		Enhancing replication of the HCV/biomarker for the hepatitis and HCC	Z. Zhang, Meng, et al. (2014)
miR‐320c	Up	Human		qRT‐PCR	ADAMTS5	Indicators of HCV‐induced liver damage	Shwetha et al. (2013)
hsa‐miR‐744	Up	Human		Microarray	Wnt signaling pathway	Reduce apoptosis/HCV‐associated activation of Wnt signaling	Poortahmasebi et al. (2016)
miR‐200b	Down	HCC tissue samples Mice Cell line	42		BMI1	Suppressor	W. R. Wu et al. (2016)
miR‐141	Up	Cell line			DLC‐1	Oncogenic	Banaudha et al. (2011)

Note. HCC: hepatocellular carcinoma; HCV: hepatitis C virus; RT‐qPCR: real‐time quantitative polymerase chain reaction.

7. EXOSOMES AND miRNAs IN HCC

Exosomes are small intraluminal vesicles (30–150 nm) that are derived from the internal multivesicular bodies and secreted from the most cell types. Also, exosomes have been observed in various body fluids (i.e., serum, urine, breast milk, saliva, synovial fluid, and malignant ascites). Moreover, exosomes contain RNAs, proteins, and viruses that have been shown to be distributed all over the body (Sohn et al., 2015). It has been indicated that HCC‐derived exosomes can regulate TAK1 expression and related signaling and elevate transformed cell growth by transferring miRNAs to the recipient cells. As well as, these exosomes could potentially help to local spread, multifocal growth in HCC or intrahepatic metastases (Kogure, Lin, Yan, Braconi, & Patel, 2011). H. Wang, Hou, et al. (2014) indicated that overexpression of miR‐21 in serum exosomes patients with HCC or CHB and studied the potential importance of miR‐21. In this study, the miR‐21 levels in serum exosomes were significantly higher than supernatant without exosome or the whole serum. Also, the expression level of serum exosomal miR‐21 in patients with HCC was significantly higher than CHB or healthy volunteers. Further, the elevated level of miR‐21 expression related to advanced tumor stage and cirrhosis. Qu et al. (2017) indicated that serum level exosomal miR‐665 was significantly higher in HCC patients compared with control subjects and significantly overexpressed in tumors larger in size. Also, in the group of patients with high levels of exosomal miR‐665, survival time was shorter than of the miR‐665 low‐expression group (Qu et al., 2017). By identifying exosomal‐derived markers, such as miRNAs, can serve as beneficial noninvasive markers, we are able to identify different stages of the malignancies and prediction of response to treatment in patients (Table 5).

Table 5.

Exosome and HCC

microRNAs	Expression	Exosome source	Detection technique	Sample (n)	References
miR‐584	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐367	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐517c	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐378	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐133b	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐376a	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐215	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐518d	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐451	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐520f	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐142–5p	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐486–5p	Up	SMMC‐7721 cells			J. Wei et al. (2015)
miR‐10b‐5p	Up	SMMC‐7721 cells			J. Wei et al. (2015)
miR‐18a	Up	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐224	Up	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐222	Up	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐221	Up	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐21	Up	Serum	qRT‐PCR	30	H. Wang, Hou, et al. (2014)
miR‐221	Up	Serum	qRT‐PCR	100 (520 HBV+50 HCC)	Y. Li et al. (2015)
miR‐191	Up	Serum	qRT‐PCR	100 (520 HBV+50 HCC)	Y. Li et al. (2015)
miR‐181a	Up	Serum	qRT‐PCR	100 (520 HBV+50 HCC)	Y. Li et al. (2015)
miR‐26a	Up	Serum	qRT‐PCR	100 (520 HBV+50 HCC)	Y. Li et al. (2015)
miR‐27b‐3p	Up	HCC cell lines	Small RNA sequencing		J. Wei et al. (2015)
miR‐92a‐3p	Up	HCC cell lines	Small RNA sequencing		J. Wei et al. (2015)
let‐7c‐5p	Down	SMMC‐7721 cells	Small RNA sequencing		J. Wei et al. (2015)
let‐7d‐5p	Down	SMMC‐7721 cells	Small RNA sequencing		J. Wei et al. (2015)
let‐7b‐5p	Down	SMMC‐7721 cells	Small RNA sequencing		J. Wei et al. (2015)
miR‐106b	Down	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐195	Down	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐122	Down	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐101	Down	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐718	Down	Serum	qRT‐PCR	59	Sugimachi et al. (2015)
miR‐9–3p	Down	Serum	qRT‐PCR		J. Tang et al. (2017)
miR‐21	Up	Serum	qRT‐PCR	30	H. Wang, Hou, et al. (2014)
miR‐665	Up	Serum HCC tissue	Microarray	30	Qu et al. (2017)
miR‐584	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐367	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐517c	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐378	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐133b	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐376a	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐215	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐518d	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐451	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐520f	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐142–5p	Up	Hep3B cells	qRT‐PCR		Kogure et al. (2011)
miR‐486–5p	Up	SMMC‐7721 cells			J. Wei et al. (2015)
miR‐10b‐5p	Up	SMMC‐7721 cells			J. Wei et al. (2015)
miR‐18a	Up	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐224	Up	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐222	Up	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐221	Up	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐21	Up	Serum	qRT‐PCR	30	H. Wang, Hou, et al. (2014)
miR‐221	Up	Serum	qRT‐PCR	100 (520 HBV+50 HCC)	(Y. Li et al., 2015)
miR‐191	Up	Serum	qRT‐PCR	100 (520 HBV+50 HCC)	Y. Li et al. (2015)
miR‐181a	Up	Serum	qRT‐PCR	100 (520 HBV+50 HCC)	Y. Li et al. (2015)
miR‐26a	Up	Serum	qRT‐PCR	100 (520 HBV+50 HCC)	Y. Li et al. (2015)
miR‐27b‐3p	Up	HCC cell lines	Small RNA sequencing		J. Wei et al. (2015)
miR‐92a‐3p	Up	HCC cell lines	Small RNA sequencing		J. Wei et al. (2015)
let‐7c‐5p	Down	SMMC‐7721 cells	Small RNA sequencing		J. Wei et al. (2015)
let‐7d‐5p	Down	SMMC‐7721 cells	Small RNA sequencing		J. Wei et al. (2015)
let‐7b‐5p	Down	SMMC‐7721 cells	Small RNA sequencing		J. Wei et al. (2015)
miR‐106b	Down	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐195	Down	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐122	Down	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐101	Down	Serum	qRT‐PCR	60	Sohn et al. (2015)
miR‐718	Down	Serum	qRT‐PCR	59	Sugimachi et al. (2015)
miR‐9–3p	Down	Serum	qRT‐PCR		J. Tang et al. (2017)
miR‐21	Up	Serum	qRT‐PCR	30	H. Wang, Hou, et al. (2014)
miR‐665	Up	Serum HCC tissue	Microarray	30	Qu et al. (2017)
miR‐335	Up	HCC cell lines	qRT‐PCR		Sugimachi et al. (2015); F. Wang, Hongwei, et al. (2017)
miR‐939	Up	HCC cell lines	qRT‐PCR		Fornari et al. (2015); Sugimachi et al. (2015)
miR‐595	Up	HCC cell lines	qRT‐PCR		Fornari et al. (2015); Sugimachi et al. (2015)
miR‐519d	Up	HCC cell lines	qRT‐PCR		Fornari et al. (2015); Sugimachi et al. (2015)
miR‐494	Up	HCC cell lines	qRT‐PCR		Fornari et al. (2015); Sugimachi et al. (2015)
miR‐1228	Up	HCC cell lines	qRT‐PCR		Fornari et al. (2015); Sugimachi et al. (2015)
miR‐125b	Up	Serum	qRT‐PCR	Cohort 1: 30 Cohort 2: 128	W. Liu et al. (2017)
miR‐203	Up	Serum	qRT‐PCR		Kim et al. (2017)
miR‐373	Up	Serum	qRT‐PCR		Kim et al. (2017)
miR‐198	Down	Serum			Devhare and Ray (2017)
miR‐320a	Down	HCC cell lines	qRT‐PCR		Z. Zhang, Li, et al. (2017)

Note. HCC: hepatocellular carcinoma; qRT‐PCR: quantitative real‐time polymerase chain reaction.

8. CONCLUSION

HCC is a complex disease, in which a variety of internal and external risk factors are involved in the beginning and development of it. It has been shown that various viruses such as HBV and HCV and other risk factors are involved in HCC pathogenesis. Deregulation of several signaling pathways such as miRNAs, PTEN, VEGF, MAPK, and EGFs could affect the progression of HCC. Among various targets, miRNAs as epigenetic regulators have critical roles in HCC pathogenesis. They act as a tumor suppressor or oncogene, which led to induced or inhibited HCC progression. Hence, it seems that more understanding of miRNA roles in HCC could contribute to designing better therapeutic approach in HCC treatment. Moreover, several studies indicated that exosomes play key roles in a variety of important biological processes (i.e., angiogenesis, growth, metastasis, cell proliferation, and response to therapy) related to HCC progression. Hence, exosomes could be introduced as a new diagnostic and therapeutic option in patients with HCC.