Resistin: an inflammatory cytokine with multi-faceted roles in cancer

Abstract

Systemic and organ-confined inflammation has been associated with cancer development and progression. Resistin, initially described as an adipocyte-derived cytokine in mice, is mostly expressed by the macrophages in humans. It has potent pro-inflammatory properties, and its elevated serum levels are detected in cancer patients. Aberrant expression of resistin receptors is also reported in several malignancies and associated with aggressive clinicopathological features. Several lines of evidence demonstrate that resistin, acting through its different receptors, promotes tumor growth, metastasis, and chemoresistance by influencing a variety of cellular phenotypes as well as by modulating the tumor microenvironment. Racially disparate expression of resistin has also attracted much interest, considering prevalent cancer health disparities. This review discusses the aberrant expression of resistin and its receptors, its diverse downstream signaling and impact on tumor growth, metastasis, angiogenesis, and therapy resistance to support its clinical exploitation in biomarker and therapeutic development.

1. Introduction

Cancer remains the second most common cause of death in the United States and worldwide [1, 2]. According to an estimate by the American Cancer Society, about 1,806,950 new cancer cases and nearly 606,520 cancer-related deaths are projected for this year in the United States [3]. Cancer is a complex disease driven through a variety of mechanisms. In many cases, its asymptomatic progression results in the late diagnosis and limiting therapeutic options. Further, the genetically advanced nature of cancer cells and intra-tumoral heterogeneity lead to the failure of most therapies. These challenges enforce the need for a better understanding of tumor biology and characterization of associated molecular factors that drive cancer development, aggressive progression, and therapeutic resistance.

Inflammation has been intricately linked with cancer either as a cause or consequence [4, 5]. An inflammatory milieu supports sustenance and accumulation of genomic aberrations and thus the initiation and progression of cancer [6, 7]. In general, inflammation is a protective arm of the immune system that protects us from external threats and helps in the healing of the damaged tissue. However, unresolved chronic inflammation, induced by abnormal immune reactions, infections that perpetuate, or conditions such as obesity, can support the process of carcinogenesis. The relevant epidemiological and clinical data exists to suggest that chronic inflammation leads to the development of cancer and is associated with aggravated clinicopathological features [7–9]. Indeed, about 25% of all cancers are etiologically linked to chronic inflammation and infection [10]. Obesity has also been associated with several types of cancer [11, 12]. Excessive accumulation of macronutrients in the adipose tissues causes the release of inflammatory mediators and thus creates a pro-inflammatory tumor supportive environment. Similarly, Helicobacter pylori infection induces pro-inflammatory gene expression leading to chronic gastritis and peptic ulceration and promotes gastric carcinogenesis [13]. Chronic inflammation is mediated through a variety of cytokines and hormones, which are also implicated in cell proliferation, apoptosis resistance, invasion, angiogenesis, and metastasis [10]. Indeed, tumor microenvironment (TME) contains a variety of non-tumor cells, including the immune cells (resident and infiltrated) that support tumor development by producing growth factors and cytokines [14–16].

In recent years, several reports have published that describe multi-faceted roles of resistin influencing almost all the critical hallmarks of cancer. Resistin is an inflammatory cytokine mostly expressed by the macrophages in humans, although it was initially described as an adipocyte-derived cytokine in mice [17]. It has potent pro-inflammatory properties and is shown to promote cancer progression either directly or indirectly [18–21]. Elevated levels of resistin were observed in the serum of obese individuals [22, 23]. Also, a considerable amount of (experimental and epidemiological) evidence suggests an association between increased resistin levels and obesity-associated malignancies [18, 24]. However, the mechanistic link of this association is not clearly understood. In this review article, we discuss the aberrant expression of resistin and its receptors in cancer, diverse downstream signaling of resistin and its impact on tumor growth, survival, metastasis, angiogenesis, and therapy resistance in multiple malignancies.

2. Resistin and its downstream signaling

Resistin is a member of the resistin-like molecule family (RELMs) that includes three additional proteins, RELM-α, RELM-β, RELM-y [25]. The name ‘resistin’ was introduced in 2001 to describe a novel adipocyte-derived molecule that resisted insulin action and promoted glucose tolerance in rodents [26]. In another more recent study, resistin was associated with lung inflammation and named as ‘Found in Inflammatory Zone 3’ (FIZZ3) protein [27, 28]. Resistin is almost exclusively expressed in white adipocytes in mice, whereas macrophages are the primary source in humans [29, 30]. The gene encoding for resistin is localized on chromosome19p13.3 and 8A1 in humans and mice, respectively [31]. The genomic organization is more or less conserved between the two species except for an extra intron of 2279 nucleotides in mice following the stop codon. This intronic region contains several regulatory sites that could have a possible role in the different expression patterns of both the resistin [32]. Resistin shares 59 % homology at the protein level between human and mouse forms [17, 32]. Mouse resistin is an 11 kilo Dalton (kDa) polypeptide, which is synthesized as a 114 amino acid (aa) precursor consisting of a 20 aa signal sequence and a 94 aa mature segment [31]. On the other hand, human resistin is a 12.5 kDa polypeptide with 108 aa mature segment [31]. Resistin contains a 10–11-cysteine-rich motif at the carboxyl-terminal (C-terminal) in both mice and humans that promotes the assembly of the globular domain through the formation of disulfide bonds [33]. This C-terminal globular head domain is the receptor-binding region, which is linked with the N-terminal or tail domain by a flexible neck domain [33, 34] (Figure 1).

Figure 1.

Structure of human resistin: Cartoon view of trimeric structure of resistin showing C-terminal globular domain containing antiparallel β-sheets and N-terminal α-helical domain linked by a flexible neck domain. The structure was predicted using the SWIS-MODEL program (https://swissmodel.expasy.org) [37] and drawn using PyMoL software.

To date, four distinct functional receptors have been identified for resistin, namely adenylyl cyclase-associated protein 1 (CAP1), toll-like receptor 4 (TLR4), an isoform of decorin (ΔDCN), and receptor tyrosine kinase-like orphan receptor 1 (ROR1). Resistin exhibits differential binding affinity towards these receptors leading to the activation of diverse cell signaling pathways (Figure 2). CAP1 and TLR4 have been the most studied resistin receptors. CAP1 is an actin-binding protein consisting of 475 aa with a carboxy-terminal domain that binds to actin, a central proline-rich domain, and an amino-terminal domain of the unknown function [35, 36]. CAP1 was first identified as a resistin receptor in human monocytes, where it mediated inflammatory actions [34].

Figure 2. Resistin signaling pathways in cancer.

Resistin binding to the transmembrane Toll-like receptor 4 (TLR4) and adenylyl cyclase-associated protein 1 (CAP1) receptors activates several signaling pathways leading to the cancer cell proliferation, invasion, migration, angiogenesis, apoptosis inhibition, and therapy resistance. Akt: Protein Kinase B; cAMP: Cyclic adenosine 3′,5′-monophosphate; EGFR: Epidermal growth factor receptor; ERK: extracellular-signal-regulated kinase; IRAK: Interleukin-1 receptor-associated kinase; IRF: Interferon Regulatory Factor; JNK: c-Jun N-terminal kinase; MAPK: Mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; MyD88: Myeloid differentiation primary response 88; NF-κβ: nuclear factor κβ; PKA: Protein kinase A; PKC: Protein kinase C; PI3K: phosphoinositide 3-kinase; p70 S6K: 70-kDa ribosomal protein S6 kinase; ROR1: Receptor Tyrosine Kinase Like Orphan Receptor; SP-1: specificity protein-1(transcription factor); SRC: Proto-oncogene tyrosine-protein kinase; STAT 3: transducer and activator of transcription 3; TIRAP: TIR Domain Containing Adaptor Protein; TRAF6:TNF receptor-associated factor 6; TRAM: TRIF-related adaptor molecule; TRIF: TIR-domain-containing adapter-inducing interferon-β.

Binding of resistin to the CAP1 upregulated intracellular cAMP concentration, enhanced Protein Kinase A (PKA) activity, and promoted NF-κβ -mediated transcription of inflammatory cytokines (IL-6, TNF-α, and IL-1B). Another study in mouse liver cells demonstrated that CAP1 mediated resistin-induced expression of genes involved in insulin resistance, inflammation, and apoptosis [38]. We also showed that resistin promoted the growth, aggressiveness, and stemness of breast cancer (BC) cells through overexpression and activation of transducer and activator of transcription 3 (STAT3) [39, 40]. Interaction of TLR4 with resistin was first reported in a human epithelial kidney cell line where it mediated the pro-inflammatory effects [41]. Resistin-TLR4 interaction induced structural changes in rat hypothalamus leading to the activation of JNK and P38 pathways via adaptor protein, myeloid differentiating factor 88 (MyD88), and Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) [42]. Further, resistin-TLR4 interaction activated porcine alveolar macrophages via the TLR4/NF-κβ pathway [43]. It also induced STAT3 and NF-κβ signaling in BC cells leading to the acquisition of epithelial-to-mesenchymal transition (EMT) and stemness [19].

Decorin is an extracellular-matrix protein that belongs to the small leucine-rich proteoglycan (SLRP) family and is involved in cell adhesion, migration, and proliferation [44, 45]. Murine resistin is shown to interact with an isoform of decorin (ΔDAC) expressed on the adipose progenitor cells [45]. Binding of resistin to decorin induced cell proliferation and migration, leading to the expansion of white adipose tissue [45]. Receptor Tyrosine Kinase Like Orphan Receptor (ROR1) belongs to a family of tyrosine kinase receptors that are important for cell division, proliferation, angiogenesis, migration, and survival [46, 47]. The ROR1 was shown to interact with murine resistin in 3T3-L1 preadipocytes leading to the activation of extracellular signal-regulated kinases 1 and 2 (ERK 1/2). It also upregulated the suppressor of cytokine signaling 3 (SOCS3) and glucose transporter 4 to promote adipogenesis and glucose uptake [46]. However, in humans, the expression of ROR1 and decorin is rarely observed in mononuclear and macrophage cells [34].

3. Aberrant expression and regulation of resistin and its receptors in cancer

Aberrant expression of resistin and resistin receptors has been reported in multiple malignancies. More importantly, it was demonstrated that resistin levels are disparately higher in African American (AA) BCpatients, suggesting its role in racially disparate clinical outcomes [39]. An earlier study also reported resistin to be one of the differentially-expressed genes in breast tumors from AA and Caucasian American (CA) patients [48]. Elevated serum levels of resistin were also reported in stage II or III BC patients treated with chemotherapy [49]. In another study, a high level of resistin in BC tissues correlated with aggressive clinicopathological features and poor survival of patients [50]. Analysis of the TCGA database found elevated expression of resistin transcripts in the estrogen receptor (ER) negative BC subtype in AA women [51]. Higher expression of resistin is also reported in lung adenocarcinoma compared to the normal lung tissues [52]. In another study, enhanced immunostaining of resistin was observed in the marginal areas of human lung cancer (LC) tissue sections [53]. Increased serum levels of resistin are reported in endometrial cancer patients as well [54]. Elevated level of resistin has been reported among other adipocytokines and inflammatory cytokines in obese people and associated with increased risk of colorectal cancer (CRC) [55, 56]. In other studies, patients with CRC exhibited higher levels of circulating resistin as compared to the control subjects [57, 58]. Apart from the resistin, increased levels of its receptor, CAP1 was also reported in CRC and suggested to be involved in the pathogenic process via interaction with resistin [59]. Overexpression of CAP1 is also associated with disease progression in BC patients [60, 61].

Enhanced expression of CAP1 in pancreatic cancers (PC) was suggested to be involved in the aggressive behavior of (PC) cells [62]. CAP1 overexpression was also found to be associated with Hepatocellular carcinoma (HCC) metastasis and poor prognosis [63]. The upregulation of the CAP1 level was also reported in invasive esophageal squamous cell carcinoma (ESCCs) and was associated with lymph node metastasis and patient’s survival [64]. BC tumor tissue exhibited significantly higher expression of TLR4 [65]. Importantly, the expression of TLR4 was associated with BC metastasis [65]. Yang et al. showed that TLR4 expression is vital for BC cell proliferation [66]. Furthermore, knockdown of TLR4 leads to the inhibition of proliferation and survival of BC cells [66]. Increased expression of TLR4 at mRNA and protein levels was also reported in LC tissue [67]. High expression of TLR4 and MyD88 has been associated with liver metastasis, and association of both was also considered to an independent predictor of poor survival in CRC patients [68]. The aberrant expression of another receptor of resistin, decorin, was also shown to drive the progression of oral epithelial cells to carcinoma [69]. Also, the enhanced expression of ROR1 in BC was found to be associated with EMT, metastasis, and increased rates of relapse [70]. It was also shown that there is an increased expression of ROR1 following treatment with chemotherapy [71]. Importantly, higher expression of ROR1 was also associated with BC stemness [71]. Moreover, exposure of HER2⁺ BC cells to T-DM1 induced ROR1 expression that was associated with increased BC stem cell phenotypes [72]. Furthermore, high ROR1 levels were shown to promote leukemia cell survival and accelerate disease progression [73]. Altogether, these evidences showed that aberrant expression of resistin receptors could lead to the progression of cancer; however, extensive studies focusing on resistin and its receptor interaction should be investigated to establish a broader and more precise clinical relevance of resistin signaling in cancer.

4. Role of resistin in cancer

The development of cancer to metastatic disease is a multi-step process. There are several hallmarks of cancer, including the ability to sustain proliferation, resist apoptosis, avoid immune destruction, unlimited replicative potential, tumor-promoting inflammation, angiogenesis induction, activation of invasion and metastasis, genomic instability and deregulated cellular energetics [74–78]. Numerous lines of evidence suggest that resistin plays a significant role in the pathogenesis of different types of malignancies by impacting on these cancer hallmarks (Figure 3). Also, the role of resistin has been suggested in therapeutic resistance as well. Below we discuss these findings in detail.

Figure 3. Role of resistin in cancer.

Inflammatory cytokine ‘resistin’ influence the pathobiology of cancer by inducing invasion, metastasis, epithelial to mesenchymal transition and stemness, angiogenesis, therapy resistance, and regulating cell cycle progression and apoptosis.

4.1. Cell cycle regulation and apoptosis-resistance

The cell cycle is a tightly controlled process that consists of the interphase and the mitotic phase. During interphase, cells prepare themselves for the cell division (the mitotic phase), and it is further subdivided into Gap 1(G1), Synthesis (S), and Gap 2 (G2) phases. The cellular transition from one phase to another is tightly regulated by cyclins and cyclin-dependent protein kinase (Cdks), whose expression is controlled by several growth-promoting and suppressive proteins, mostly transcription factors or their co-factors [79–87]. It appears that resistin may affect the cell cycle in a context-dependent manner. One study shows that resistin activates ERK via the activation of the TLR4-MyD88-dependent pathway. Activation of ERK promotes the upregulation of SOCS 3 that downregulates the JAK2/STAT3 pathway leading to the arrest of cells in the G1 phase. The arrest of resistin-exposed cells in the G1 phase helped them survive 5-fluorouracil treatment due to a decrease in drug uptake [88]. These findings are intriguing because many other reports show a growth-promoting action of resistin on cancer cells [39, 89, 90]. Resistin promoted prostate cancer cell proliferation through the activation of PI3K/Akt signaling [91]. Akt pathway plays a significant role in inhibiting cell cycle arrest by phosphorylating p21[92].

Apoptosis, also known as “programmed cell death,” is another growth regulatory process that maintains cellular homeostasis by getting rid of aging cells during the process of development [93]. Apoptosis is also induced when cells experience cellular or genetic damage under a disease condition to keep a check on the propagation of defective cells [94]. This regulatory process is lost or weakened in all cancer cells because of genomic or aberrant activation of various survival signaling pathways [95, 96]. In several studies, resistin has been implicated in the activation of the anti-apoptotic pathways and supports tumor cell survival. In myeloma cells, resistin upregulated NF-κB and PI3K/Akt pathways to reduce the apoptosis [97]. This study also showed that resistin enhanced the expression and drug efflux function of ATP-binding cassette (ABC) transporters via decreasing the expression and methylation levels of both DNA methyltransferases, DNMT1, DNMT3a and ABC gene promoters leading to the inhibition of chemotherapy-induced apoptosis. Overexpression of resistin in LC cells is also shown to confer apoptosis resistance as a decrease in the apoptosis-associated proteins caspase-3, and caspase-7 expression [52]. Activation of the MAPK/ERK, JAK/STAT, and Akt/PI3K signaling pathways by resistin led to apoptosis inhibition in porcine ovarian cells [98]. This study further showed that resistin decreased the expression of proapoptotic genes FADD, FAS, and CASP8 in ovarian cells. Overall, these findings suggest that resistin promotes the growth of cancer cells by impacting both cell cycle and apoptotic processes through a variety of mechanisms.

4.2. Cell invasion and metastasis

The gain of a motile and invasive phenotype is essential for a malignant cell to grow optimally at the primary site as well as metastasize to the distant locations via facilitating their intravasation and extravasation [99, 100]. Resistin is shown to promote the invasion and metastasis of lung adenocarcinoma cells through mechanisms involving the activation of TLR4/Src/EGFR/PI3K/NF-κβ signaling pathway [101]. Resistin also activates the ezrin, radixin, and moesin (ERM) protein to promote migration and invasion of BC cells [102]. Activation of ERM proteins occurred via calcium-mediated Src/PP2A/PKCα signaling that also enhanced the expression of vimentin, a protein associated with the gain of malignant phenotype [102]. In our earlier lab study, we found that resistin promoted the migration and invasion of BC cells by enhancing the expression and phosphorylation of STAT3 [39]. We further found that resistin promoted IL-6 expression and secretion that was involved in resistin-induced STAT3 phosphorylation. Resistin is shown to elicit the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) via NF-κB pathway in hepatic carcinoma cells to facilitate their adhesion to endothelium and subsequent metastasis [103]. In CRC, resistin treatment increased the adhesion of cancer cells to endothelial cells via the activation of the NF-κB pathway and the expression of ICAM-1A and VCAM-1 [104]. Resistin also increased invasion in multiple liver cancer cell lines by promoting the phosphorylation of Akt and ERK signaling pathway [105]. The invasive potential of ovarian cancer (OC) cells was also increased by resistin through the inhibition of tumor suppressor miRNAs, including, let-7a, miR-200c, and miR-186 [89]. Rosendahl et al. demonstrated that adipocyte secretome promotes BC cell proliferation and motility [106]. Besides, resistin was directly associated with the differentiation of osteoclasts, which played an important role in LC bone metastasis [53]. Moreover, resistin upregulated the expression of TWIST that is known to promote the metastasis of LC cells [107, 108]. Furthermore, binding of resistin to CAP1 or TLR4 led to STAT3 activation and induced migration and invasion of (PC) cells [20]. Altogether, significant data support the role of resistin mediated signaling in tumor cell invasion and metastasis.

4.3. Epithelial-to-mesenchymal transition (EMT) and cancer stemness

Elizabeth Hay postulated the concept of EMT more than 50 years ago [109]. During EMT, epithelial cells transition into a mesenchymal phenotype through a series of biochemical and molecular changes, and this process is often associated with the gain of invasiveness and stemness properties [110, 111]. Acquisition of stem cell-like properties by cancer cells is also associated with their ability to sustain under stressed environmental conditions [112–114]. EMT and cancer stemness potential are regulated by the interplay of several signaling pathways culminating into the altered expression and activation of gene regulators, including transcription factors and miRNAs [115–119]. Activation of TGF-β, NOTCH, Hedgehog pathway, and Wnt pathways serve as a biochemical switch for EMT and gain of cancer stemness properties [119]. Their effect is mediated through a variety of transcription factors, including Zeb, Snail, and Twist, that eventually alter the expression of cadherin proteins and other proteins involved in cellular polarization [119]. We recently demonstrated that treatment of BC cells with resistin led to the activation of STAT3 as well as the overexpression of other stemness associated transcription factors Nanog and KLF4 [40]. In another study, the interaction of resistin with TLR4 was shown to mediate the activation of STAT3 and NF-κβ in BC cells leading to the induction of EMT and stemness phenotype [19]. Resistin has been reported to upregulate other transcription factor proteins involved in EMT and cancer stemness, including SNAIL, SLUG, ZEB1, and TWIST1, that alter the expression of fibronectin, vimentin, E-cadherin and claudin-1 [120]. Resistin also promotes EMT and stemness in OC cells through a miRNA-mediated mechanism [89].

4.4. Angiogenesis

Angiogenesis is the process of formation of new blood vessels from the existing ones. It is a complicated process that requires extracellular matrix degradation, increase vascular permeability, proliferation, migration, and invasion of endothelial cells, followed by the formation of new vessels [121, 122]. Angiogenesis is an essential requirement for optimal cancer growth. As the tumor grows, its demand for nutrients and oxygen increases, and thus cancer cells secrete factors to stimulate the process of angiogenesis [122, 123]. Inflammatory TME can further promote this process. Resistin was shown to induce the expression of VEGF and MMP2 in human ovarian epithelial cancer cell lines to promote angiogenesis [124]. Resistin induced the expression of VEGF-C and downregulated miR-186 in chondrosarcoma to promote lymphangiogenesis [125]. In another study, resistin promoted VEGF-A production in chondrosarcoma cells by decreasing miR-16–5p via PI3K/Akt-dependent signaling pathway to induce proliferation of endothelial progenitor cells (EPCs) [126]. Resistin is also reported to induce angiogenesis by promoting human coronary artery endothelial cells (HCAECs) proliferation, migration, and capillary-like tube formation, upregulating the expression of vascular endothelial growth factor receptors (VEGFRs) and matrix metalloproteinases (MMPs) and activating ERK1/2 and p38 pathways [127]. Also, treatment of human umbilical vein endothelial cells (HUVECs) with resistin led to the induction of VEGF production and increased endothelial cell tube formation in an in vitro model [128].

4.5. Therapeutic resistance

Therapeutic-resistance is a significant cause of cancer-associated mortality. A plethora of literature now suggests that TME plays a vital role in cancer growth and therapeutic-resistance and thus needs to be exploited [78, 129–131]. Resistin increased the expression and drug efflux function of ABC transporters in myeloma by relieving its epigenetic repression via DNA methyltransferases (DNMT1 and DNMT3a) [97]. Overexpression of ATP-binding cassette (ABC) transporters has been associated with inherent and acquired multidrug resistance in several cancers [132–134]. Resistin was also shown to upregulate the levels of fatty acid synthase (FASN), caveolin (Cav)-1, and P-glycoprotein (P-gp) in myeloma that associated with resistance to dacarbazine (DTIC) therapy [90]. Resistin also induces the expression of stemness-associated factors, KLF4, and Nanog, which have been implicated in doxorubicin resistance [40]. We also demonstrated that resistin treatment of BC cells reduced their sensitivity to doxorubicin in through STAT3 activation. Autophagy is a conserved process of self-destruction employed by cells to degrade and generate new organelles [135]. The induction of autophagy also enables cancer cells to resist drug-induced toxicity [135, 136]. Resistin was shown to induce autophagy in BC cells as a mechanism to survive during doxorubicin treatment [137]. Mechanistic studies revealed that the induction of autophagy by resistin was mediated through the activation of AMPK/mTOR/ULK1 and JNK signaling pathways. Resistin is also reported to confer cisplatin-resistance in OC cells by downregulating miRNAs let-7a, miR-200c, and miR-186 [89]. The role of resistin in the progression of several cancers is summarized in Table 1.

Table 1:

Role of resistin in different cancers

Type of cancer	Effect	Mechanism of action	References
Breast	Invasion and Migration	Calcium-dependent c-Src and PKCα-ezrin pathway	[102]
	Metastasis	Induction of EMT and stemness	[120]
	Doxorubicin-resistance	AMPK/mTOR/ULK1 and JNK signaling pathways	[137]
	Chemoresistance and stemness	STAT 3 pathway	[40]
	Progression	Induction of EMT and stemness by TLR4/NF-κB/S TAT3 signaling pathway	[19]
Colorectal	CRC stage progression	Higher levels of resistin	[138]
	G1 arrest of cells	ERK/ SOCS3/ JAK2/STAT3 pathway	[88]
	Inhibition to apoptosis by 5-fluorouracil	G1 arrest of cells	[88]
	Endothelial adhesion	NF-κβ pathway and expression of ICAM-1A and VCAM-1	[104]
Myeloma	Multidrug resistance	NF-κB and PI3K/Akt pathways and ABC transporter	[97]
Ovarian	Angiogenesis	PI3K/Akt-Sp1 pathway and VEGF expression	[124]
	Invasion and Cisplatin-resistance	Induction of EMT and stemness by tumor suppressor miRNAs, let-7a, miR-200c, and miR-186	[89]
Gastric	SDF-1 expression	p38 MAPK and NF-κβ pathway	[139]
Prostate	Cell proliferation	PI3K/Akt signaling pathways	[91]
Liver	Adhesion to human umbilical vein endothelial cells (HUVECs)	NF-κB-regulated ICAM-1 and VCAM-1 expression	[103]
Pancreatic	Proliferation, migration, invasion and gemcitabine resistance	STAT3 signaling pathway	[20]
Lung	Development and metastasis	Expression of Wolf-Hirschhorn syndrome candidate 1 (WHSC1) histone methyltransferase and TWIST	[53]
	Invasion and metastasis	TLR4/Src/EGFR/PI3K/NF-κβ pathway	[101]

5. Conclusion and future perspectives

Resistin has emerged as an important inflammatory cytokine over the past two decades. A growing body of evidence also supports an association of resistin in cancer pathogenesis and therapeutic outcomes. Resistin not only enhances the growth and aggressiveness of cancer cells but is also involved in diminishing the therapeutic efficacy of several anti-cancer drugs. Higher circulating levels of resistin positively correlate with increased tumor stage, size, and lymph node metastasis in various cancer subtypes. Therefore, it would be interesting to see if resistin could be useful as a potential clinical biomarker in cancer. Since enhanced levels of resistin can be detected under various inflammatory conditions, including obesity, it may not alone be used as a specific diagnostic marker. However, it could still be useful in predicting the risk of cancer development, especially in people who are already genetically predisposed. Further, considering the role of resistin in cancer aggressiveness and therapy-resistance, its utility as a prognostic biomarker and therapeutic response predictor could be explored. Therapeutic targeting of resistin would also be challenging due to its interaction with multiple known receptor proteins and diverse impact on downstream signaling pathways. It is crucial that we develop a precise mechanistic understanding of resistin action in cancer cells and identify the protein that mediates or modify its effect on cancer phenotypes. It is also important that we characterize all the proteins that bind to resistin and can positively or negatively influence its downstream oncogenic signaling. More and more studies are needed to study the collective clinical significance of resistin and its known receptors in cancer. Overall, resistin and its interactors hold great significance in the clinical management of cancer. Inhibiting the effects of resistin on cancer cells, either by neutralizing antibody, antagonism of resistin receptor or by antisense oligonucleotides or RNA interference, could be useful therapeutic strategies against cancer. Targeting mechanisms regulating resistin and its receptors could also be useful in cancer prevention and therapy. Thus, biological understanding of resistin action and careful strategizing for the development of therapeutics targeting resistin and its receptor axis has enormous implications in the effective management of cancer.

Highlights.

• Inflammation is intricately linked with cancer either as a cause or a consequence.

• Resistin is a pro-inflammatory cytokine whose serum levels are elevated in cancer patients.

• Aberrant expression of resistin receptors is also reported in cancer and associated with disease aggressiveness.

• Resistin signaling plays multiple roles in cancer development and could be exploited for cancer prevention and therapy.

Abbreviations:

CAP1

adenylyl cyclase-associated protein 1

DMT

DNA methyltransferases

ER

estrogen receptor

ERK

extracellular-signal-regulated kinase

EMT

epithelial-to-mesenchymal transition

ERM

ezrin, radixin, and moesin

FIZZ3

found in Inflammatory Zone 3

ICAM-1

intercellular adhesion molecule-1

JNK

c-Jun N-terminal kinase

MyD88

myeloid differentiating factor 88

NF-κβ

nuclear factor κβ

PKA

protein kinase A

ROR1

receptor tyrosine kinase-like orphan receptor 1

SLRP

small leucine-rich proteoglycan

SOCS3

suppressor of cytokine signaling 3

STAT3

transducer, and activator of transcription 3

TIRAP

toll/interleukin-1 receptor domain-containing adaptor protein

TLR4

toll-like receptor 4

TME

tumor microenvironment

VCAM-1

vascular cell adhesion molecule