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. 2019 Jan 3;19:5. doi: 10.1186/s12935-018-0723-8

Relationship between the upregulation of Notch1 signaling and the clinical characteristics of patients with papillary thyroid carcinoma in East Asia: a systematic review and meta-analysis

Libing Yuan 1,#, Lei Ma 2,#, Haibo Xue 1,✉,#, Shoujun Song 1
PMCID: PMC6317185  PMID: 30622441

Abstract

Background

Many studies have aimed to clarify the relationship between Notch1 signaling and papillary thyroid carcinoma (PTC), but the results have been inconsistent to date. In the present study, a systematic review and meta-analysis were performed to analyze the relationship between Notch1 signaling and the clinical characteristics of PTC.

Methods

Literature databases, including PubMed (Medline), Embase and China National Knowledge Infrastructure, were searched for relevant studies from inception to April 2018. A total of five studies, including 421 patients with PTC from China and South Korea, were included in the meta-analysis.

Results

The results revealed that the upregulation of Notch1 signaling was positively correlated with lymph node metastasis in patients with PTC (OR = 3.25, 95% CI 1.14–9.23, P = 0.03). Additionally, positive correlations were found between Notch1 signaling and tumor size (OR = 4.34, 95% CI 1.66–11.38, P = 0.003), capsular invasion (OR = 3.49, 95% CI 1.90–6.41, P < 0.0001) and clinical stage of PTC (OR = 2.31, 95% CI 1.05–5.11, P = 0.04).

Conclusions

The Notch1 signaling pathway may play a catalytic role in the progression of PTC, and upregulation of Notch1 signaling may have significant predictive value for the clinical prognosis of PTC.

Keywords: Notch1 signaling pathway, Papillary thyroid carcinoma, Clinical characteristic, Meta-analysis

Background

Thyroid cancer is one of the most common malignant tumors of the endocrine organ and is the most common malignant head and neck tumor. The morbidity and mortality rates of thyroid cancer remain high among head and neck cancers and are increasing each year. Papillary carcinoma is one of the most common pathological patterns in thyroid cancer, accounting for 60%–80% of cases among Chinese adult patients and 79.3% of cases in the United States [1]. This pathological pattern is well differentiated and characterized by slow growth and low malignancy, but the disease has a multicentric occurrence tendency and may develop features such as lymphatic metastasis in the neck at an early stage [2].

With the advancement of molecular biology, the evidence for the close relationships between tumors and certain genes has grown increasingly abundant. The Notch protein family plays an important role in cell differentiation, organ development and tumor genesis, progression, invasion and metastasis [3, 4]. The Notch signaling pathway is highly conserved in the process of biological evolution, and its activation can both accelerate the genesis of cancer and restrain the genesis of cancer, which may be correlated with cell environment [5–9]. Additionally, Notch signaling plays the double roles of oncogene and anti-oncogene in human tumors. Notch-related genes were first identified as oncogenes in T-lymphocytic leukemia [10] and were abnormally expressed in multiple types of tumors in subsequent research. For example, depletion of Notch1 led to growth inhibition of ovarian cancer cells, suggesting its carcinogenic effect [11]. The activation of Notch signaling restrains the growth of prostatic cancer, small cell lung carcinoma, basal cell carcinoma and pancreatic carcinoid cells, suggesting its antitumor effects [12–15]. Apart from the process of cancer genesis, as one of the four main proteins of the Notch family, Notch1 signaling plays an important role in cancer development. Notch1 has been found in a higher state of activation in tumor cells from colorectal cancer patients with lymphatic metastasis or distant metastasis than in those at an early stage, and these cells have a higher invasion and metastasis ability [16]. Therefore, it was suggested that the activation of Notch1 signaling may play an important role in accelerating the progression and metastasis of tumors.

Human medullary thyroid carcinoma (MTC) tissue and TT cell strains of MTC could be restrained by the activation of Notch1 signaling by injecting doxycycline into mouse models of MTC, the mouse tumors demonstrated significantly slower growth than the normal control group [17]. Additionally, Notch1 had lower expression in a cell strain of follicular thyroid carcinoma (FTC), and the proliferation of cells could be restrained after transfecting the two types of cells with a plasmid expressing the Notch1 intracellular domain [18]. Therefore, Notch1 signaling could play an inhibitive role in the aforementioned two types of thyroid cancer. However, the relationship between the Notch1 signaling pathway and PTC, the most common type of malignant tumor of the endocrine organ, and the regulatory mechanism of its downstream target genes remain undefined.

The present meta-analysis, based on retrieved documents, was conducted to evaluate the correlations between Notch1 signaling and lymphatic metastasis and other clinical features of PTC, which may provide useful information for evidence-based medicine for the prognosis, prophylaxis and treatment of PTC.

Methods

Retrieval strategy

The research material was collected from published clinical case–control studies, with or without blinding. The language was limited to English and Chinese. Retrieval was conducted via a computer or retrospective database, such as PubMed (Medline), Embase and China National Knowledge Infrastructure (CNKI), from inception to April 2018. The retrieval words were papillary carcinoma of thyroid gland, papillary thyroid carcinoma, Notch1, Notch signaling, lymph node, thyroid cancer, lymphatic metastasis, tumor size, capsular invasion and clinical staging.

Inclusion criteria

(1) One-off primary studies related to PTC, Notch signaling, lymphatic metastasis, tumor size, capsular invasion or clinical staging published and unpublished. (2) Patients with PTC staging criteria conforming to the 2015 thyroid cancer National Comprehensive Cancer Network (NCCN) guidelines. (3) The literature had raw data and provided the odds ratio (OR) and 95% confidence interval (CI), or these could be obtained from the data through calculation. (4) Original documents with objectives and complete pathological diagnosis. (5) No history of other malignant tumors.

Exclusion criteria

(1) Documents with nonrigorous experiments and incorrect statistical approaches. (2) Repeatedly published thesis or research. (3) No control group. (4) Lacking an objective or complete pathological evidence.

Expression of Notch1 signal

We defined high and low Notch1 expression by immunohistochemical staining evaluation, as well as through detailed reading of the full text, contacting the author and other methods of collecting information, and after strict discussion, we excluded articles that cannot be merged, such as those with (1) unqualified primary antibodies; (2) serious interpersonal bias; (3) unscientific positive definitions; (4) grouping methods that could not be merged.

Data extraction and quality evaluation of included documents

Papers were retrieved and screened by reading their titles and abstracts, which was performed by two researchers independently. The abstracts were read to determine whether they met the criteria and eliminate unqualified literature. The information extracted included the name of the first author, year of publication, research design (e.g., sample size, randomization, allocation concealment, blinding method, pathological basis) and patient characteristics (expression of Notch1, lymph node metastasis, tumor size, capsular invasion and clinical staging). The quality of the selected papers was assessed by another two evaluators based on the Newcastle–Ottawa scale (NOS) [19]. The final score of the evaluation was the sum of the selection of the study group (4 points), the intergroup comparability (2 points) and the measurement of the exposure factors (3 points). If the opinions were inconsistent, the final score was determined by discussion, or the average value to one decimal place was the final score if agreement was not reached. Studies with a score of 0–4.5 points were classified as low quality, and those with a score of 5–9 were classified as high quality.

Statistical analysis

The meta-analysis was conducted using RevMan5.3 (Review Manager, Nordic Cochrane Centre, Danmark). The OR was used to represent the selected enumeration data, and the 95% CI of each OR was calculated and used to draw a forest map, which was named the dominance ratio map, to demonstrate differences between the results. Heterogeneity was determined by the I2 value, and only low-heterogeneity (I2 ≤ 25%) and middle-heterogeneity data (25 < I2 ≤ 75%), not high-heterogeneity data (I2 > 75%), were used for the meta-analysis.

Results

Basic features of the included studies

After the initial screening, 307 documents were retrieved; 212 remained after removing duplicates; and 109 papers were selected through the initial screening after reviewing abstracts and prefaces. By reading through the full text, we eliminated 23 unrelated documents according to our inclusion and exclusion criteria. There were 70 papers without usable data or pathological diagnostic evidence and 11 studies without case controls. Finally, five studies were chosen, including three in English and two in Chinese [20–24]. All the cases included were from China and South Korea. The process of the systematic literature search is displayed in a flow diagram in Fig. 1. The characteristics and quality evaluation of the included literature are shown in Table 1.

Fig. 1.

Fig. 1

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Literature screening process and results

Table 1.

Characteristics and quality evaluation of the included studies

Study (year) Case (n) Country Antibody for Notch1 NOS score
H. Fu (2016) [20] 68 China Cell Signaling Technology, USA 7.5
H.S. Park (2012) [22] 174 South Korea Abcam, UK 8.5
J. Zhang (2014) [23] 70 China Epitomics, USA 6
Q. Long (2012) [24] 40 China Santa Cruz, USA 6.5
M. Jing-You (2017) [25] 69 China Boosen Biotechnology, CHN 7
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Antibody for Notch1: Manufacturer of Notch1 primary antibody

NOS score Newcastle–Ottawa scale score

Results of meta-analysis and heterogeneity analysis

In the five studies, the association between Notch1 signaling and sex of patients with PTC was analyzed, and an OR of 1.24 (95% CI 0.69–2.23) was found (Z = 0.73, P = 0.47 in the test for overall effect). These data reveal that there was no significant correlation between Notch1 signaling and sex in PTC patients (see Fig. 2 for details).

Fig. 2.

Fig. 2

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Association between Notch1 signaling and sex of patients with papillary thyroid carcinoma. OR odds ratio, CI confidence interval, Event male

A total of 381 patients from five studies were analyzed to assess the relationship between Notch1 signaling and the age of patients with PTC, which was divided into two groups (≥ 45 and < 45). There was no significant association between Notch1 signaling and age (OR = 1.15, 95% CI 0.53–2.51, Z = 0.35, P = 0.72) (Fig. 3). Thus, the age-related relationship between Notch1 signal and PTC has not been clarified.

Fig. 3.

Fig. 3

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Association between Notch1 signaling and age of patients with papillary thyroid carcinoma. OR odds ratio, CI confidence interval, Event more than 45 years old

The meta-analysis of the association between Notch1 signaling and lymphatic metastasis of PTC in the five studies indicated that the OR was 3.25 (95% CI 1.14–9.23), and the 95% CI of the OR fell to the right side of the vertical line in the forest map (Z = 2.21, P = 0.03 in the test for overall effect), which suggested that there was a significant correlation between Notch1 signaling and lymphatic metastasis of PTC. Therefore, Notch1 signal overexpression may accelerate lymphatic metastasis of PTC (Fig. 4).

Fig. 4.

Fig. 4

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Association between Notch1 signaling and lymph node metastasis in patients with papillary thyroid carcinoma. OR odds ratio, CI confidence interval, Event patients with lymph node metastases

Two studies were used to analyze the relationship between Notch1 signaling and the primary lesion size in patients with PTC. The patients were divided into ≤ 2 cm and > 2 cm groups according to the primary tumor size. The meta-analysis revealed an OR of 4.34 (95% CI 1.66–11.38) (Fig. 5). In the forest map, the 95% CI of the OR was on the right side of the vertical line (Z = 2.99, P = 0.003 in the overall effect test), which indicated that upregulation of Notch1 signaling may promote tumor enlargement in PTC.

Fig. 5.

Fig. 5

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Association between Notch1 signaling and the primary lesion size of patients with papillary thyroid carcinoma. OR odds ratio, CI confidence interval, Event tumor diameter greater than 2 cm

The meta-analysis of the relationship between Notch1 signaling and the clinical stage of patients with PTC in the present study was based on two articles. According to clinical stage, patients were divided into two groups (one group with stage I and II, the other group with stage III and IV). Figure 6 shows an OR = 2.31 (95% CI 1.05–5.11), and the 95% CI of the OR was on the right side of the vertical line in the forest map (Z = 2.07, P = 0.04). These data suggest that overexpression of Notch1 may promote the invasion, expansion or metastasis of PTC.

Fig. 6.

Fig. 6

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Association between Notch1 signaling and the clinical stage of patients with papillary thyroid carcinoma. OR odds ratio, CI confidence interval, Event stage I and stage II patients

A total of 309 patients from three articles were analyzed to assess the association between Notch1 signaling and capsular invasion of PTC. The OR was 3.49 (95% CI 1.90–6.41), and the 95% CI of this OR fell to the right side of the vertical line in the forest map (Z = 4.03, P < 0.0001 in the test for overall effect). These findings demonstrate that upregulation of the Notch1 signaling pathway may contribute to the process of primary tumor capsular invasion in PTC (Fig. 7).

Fig. 7.

Fig. 7

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Association between Notch1 signaling and capsular invasion in patients with papillary thyroid carcinoma. OR odds ratio, CI confidence interval, Event patients with capsular infiltration

Discussion

The Notch signaling pathway is involved in not only the normal development of the nervous and endocrine systems but also tumorigenesis in multiple tissues, including hematologic, breast, prostate, cervix, lung, liver, and brain malignancies [25–34]. In thyroid tumors, most studies on the role of Notch1 signaling have mainly investigated MTC because of the association between Notch expression and neuroendocrine development. Although PTC is the most common subtype of thyroid carcinoma, studies on the association between Notch1 signaling and its clinicopathological factors are limited.

As the most important member of the Notch family, the role of the Notch1 signaling pathway in the development of PTC is intriguing. The TNM system is the most widely adopted system for grading PTC, and large tumor size, lymph node metastasis, capsule invasion, and old age are high-risk clinicopathological characteristics in PTC. Because patients with these high-risk variables are prone to recurrence or metastasis even after operations, they are usually advised to undergo radioiodine remnant ablation (RRA) according to guidelines [35]. Therefore, we conducted the present study to determine whether there were some associations of clinical significance with the expression of Notch1 and these high-risk clinicopathological characteristics.

We pooled five studies and obtained a sample size of 421 cases of PTC in East Asia to yield more robust results. A systematic review and meta-analysis revealed that there was a significant positive correlation between lymphatic metastasis of PTC and activity of the Notch1 signaling pathway. Meanwhile, the trend of the relationship was highly consistent among the included studies, and four studies showed an estimated MHOR point of more than one. Therefore, we speculate that the activation of Notch1 signaling may promote the metastasis of PTC cells to lymph nodes. Grouping analysis was used to further evaluate the correlation between Notch1 signaling and other clinical features of PTC and revealed that Notch1 signaling was closely correlated with tumor size, capsule invasion and clinical stage in patients with PTC. Importantly, almost all the studies included in this meta-analysis suggested that higher Notch1 signaling would lead to poor prognosis in patients with PTC. The relationship trends in this analysis were highly consistent as well, and all the included studies showed a MHOR point estimate of more than one. Some previous studies reported that the downregulation of Notch1 signaling could reduce the proliferation of PTC cells [36]. Another recent study demonstrated that the activation of Notch1 signaling could promote the induction of epithelial–mesenchymal transition (EMT) and the progression of PTC [37]. These findings combined with the results of our meta-analysis suggest that upregulation of Notch1 signaling may be a valuable predictor of greater tumor diameter, higher risk of capsule infiltration and higher clinical stage in patients with PTC.

Although the incidence of PTC was higher among females according to the SEER investigation [38], we found no significant differences in the distribution of men and women among the patients with upregulated Notch1 signaling. Additionally, the patient’s age is considered an important variable for the diagnosis of Differentiated thyroid carcinoma (DTC) according to the TNM system, but we did not find any significant relationship between Notch1 signaling and age in patients with PTC in the present study, which further indicated that advanced age may be an independent risk factor for the prognosis of PTC. Moreover, it was reported that upregulation of Notch1 was involved in the chemotherapy resistance and tumor recurrence in glioblastoma [39]. Another study revealed that upregulation of Notch1 signaling was related to a higher recurrence rate in patients with PTC [40]. However, due to the inconsistent treatment methods in different studies, as well as the nonuniform diagnostic criteria for recurrence, we did not further explore the association between Notch1 signaling and the recurrence of PTC in the present meta-analysis. In addition, all the patients included were from Asia (China and South Korea), which limits the generality of our conclusions to a certain extent. More studies are needed on the activity of Notch1 signaling in patients with PTC in Europe, USA and Africa.

In summary, the results of the present study reveal that the Notch1 signaling pathway may play a catalytic role in the progression of PTC, and the activity of Notch1 signaling may be a significant predictive marker for the prognosis of PTC. Therefore, it can be suggested that PTC patients with higher Notch1 signaling activity may tend to have more tumor invasiveness and can benefit from more active treatment (such as RRA).

At present, there has been no decisive breakthrough in the study of the Notch1 signaling pathway, but there are many recent studies supporting our view. In the process of tumor invasion, the epithelial–mesenchymal transition (EMT) occurs in some cells, and tumor cells lose cell–cell adhesion. EMT leads to tumor cytoskeletal rearrangement, reduced cell rigidity and cell–cell connectivity, supporting tumor metastasis and invasion. Studies have shown that Notch receptors can be linked to myosin, thereby affecting the mechanical properties and physical ability of cells [41]. In addition, Notch1 can reduce the expression of zinc finger E-box binding homeobox (ZEB) and vimentin by regulating miR-200b, thereby promoting tumor cell EMT [42]. During cell migration, F-actin aggregates at the front edge of invasive cells and pushes the cell membrane outward to form protrusions. The protrusions are anchored in the extracellular matrix by integrin family transmembrane receptors and are coupled with actin cytoskeleton by adhesion spot proteins. ADAM12 is an anoxic effector and is regulated by Notch1. At the same time, ADAM12 is also a heparan-binding EGF-like growth factor (HB-EGF) shedding enzyme. Hypoxia activates EGFR via HB-EGF. The signaling pathway promotes the formation of invasive pseudopods, that is, hypoxia can increase the expression of ADAM12 by activating Notch1, thereby promoting the formation of invasive pseudopods induced by HB-EGF shedding [43]. Tumor cells penetrate the extracellular matrix barrier and the basement membrane of the vascular wall, and permeation of the haemorrhagic vessel wall into the host microenvironment is inseparable from the degradation of extracellular matrix and basement membrane. Matrix metalloproteinases (MMPs) are important enzymes that degrade the extracellular matrix and play an important role in tumor invasion and metastasis. MMP-2 and MMP-9 are the most important factors in the MMP family in promoting tumor invasion and metastasis. Studies have shown that activation of the Notch1 signaling pathway significantly increases the expression of MMP-2 and MMP-9 in the MMP family [44]. Inhibition of Notch1 can significantly reduce the binding ability of NF-kappa B to DNA, and the expression and activity of MMP-2 and MMP-9 are also significantly inhibited, thus reducing the metastasis ability of cancer cells. MMP-2 and MMP-9 activation enhances invasive ability [44, 45]. These results suggest that cell–cell adhesion can influence downstream gene expression through Notch1 signaling, thus altering the mechanical properties of cancer cells.

Some pathological factors, such as histological subtype, serum thyroglobulin and several other protein levels, are important and may affect the progression of PTC [46]. In the present study, the systematic evaluation suggested that the Notch1 signaling pathway has high clinical significance in the prognostic evaluation of PTC. However, a meta-analysis cannot substitute for direct evidence obtained from large-scale and multicenter randomized-controlled trials (RCTs). Furthermore, in-depth research into specific molecular mechanisms is needed to provide reliable theoretical foundations for the Notch1 signaling involvement in the pathogenesis and progression of PTC, and such mechanisms may be a new target for clinical treatment and provide predictive value in patients with PTC.

Conclusion

Here, we searched electronic databases for relevant studies, and enrolled 5 studies with a total of 421 patients for meta-analysis, drawing a conclusion that the Notch1 signaling pathway may play a catalytic role in the progression of PTC. Taken together, the results from our meta-analysis suggest that PTC patients with higher Notch1 signaling activity may tend to have more tumor invasiveness. More multi-center prospective cohorts are warranted to further validate the role of the Notch1 signaling in PTC.

Authors’ contributions

LBY, LM and HBX conceived and wrote the paper; LBY, LM and HBX collected and analyzed the data; LBY, LM, HBX and SJS revised the whole paper. All authors have reviewed the final version of the manuscript and approved to submit to your journal. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Please contact author for data requests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Funding

This study was funded by the Key Research and Development Program of Shandong Province (No. 2016GSF201021), the Science and Technology Program of Higher Education of Shandong Province (No. J16LL01) and the Natural Science Foundation of Shandong Province (No. ZR2013HM049).

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abbreviations

PTC

papillary thyroid carcinoma

CNKI

China National Knowledge Infrastructure

MTC

medullary thyroid carcinoma

FTC

follicular thyroid carcinoma

NCCN

National Comprehensive Cancer Network

CI

confidence interval

NOS

Newcastle–Ottawa scale

OR

odds ratio

RRA

radioiodine remnant ablation

EMT

epithelial–mesenchymal transition

DTC

differentiated thyroid carcinoma

RCTs

randomized-controlled trials

Contributor Information

Libing Yuan, Email: yuanlibing123@163.com.

Lei Ma, Email: doctor_malei@126.com.

Haibo Xue, Phone: +86-135 0543 9008, Email: xue_haibo@hotmail.com.

Shoujun Song, Email: songshoujun@126.com.

References

  • 1.Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–954. doi: 10.1038/nature00766. [DOI] [PubMed] [Google Scholar]
  • 2.Chung YS, Kim JY, Bae JS, Song BJ, Kim JS, Jeon HM, Jeong SS, Kim EK. Lateral lymph node metastasis in papillary thyroid carcinoma: results of therapeutic lymph node dissection. Thyroid. 2009;37(9):241–246. doi: 10.1089/thy.2008.0244. [DOI] [PubMed] [Google Scholar]
  • 3.Yap LF, Lee D, Khairuddin A, Pairan MF, Puspita B, Siar CH, Paterson IC. The opposing roles of NOTCH signaling in head and neck cancer: a mini review. Oral Dis. 2015;21(7):850–857. doi: 10.1111/odi.12309. [DOI] [PubMed] [Google Scholar]
  • 4.Garcia A, Kandel JJ. Notch: a key regulator of tumor angiogenesis and metastasis. Histol Histopathol. 2012;27(2):151–156. doi: 10.14670/hh-27.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Wang X, Jiao Z. Advances in research on Notch signaling pathway and digestive system tumors. Tumor. 2012;32(3):222–226. [Google Scholar]
  • 6.Kang M, Jiang B, Xu B, Lu W, Guo Q, Xie Q, Zhang B, Dong X, Chen D, Wu Y. Delta like ligand 4 induces impaired chemo-drug delivery and enhanced chemoresistance in pancreatic cancer. Cancer Lett. 2013;330(1):11–21. doi: 10.1016/j.canlet.2012.11.015. [DOI] [PubMed] [Google Scholar]
  • 7.Xie M, Zhang L, He CS, Xu F, Liu JL, Hu ZH, Zhao LP, Tian Y. Activation of Notch-1 enhances epithelial–mesenchymal transition in gefitinib-acquired resistant lung cancer cells. J Cell Biochem. 2012;113(5):1501–1513. doi: 10.1002/jcb.24019. [DOI] [PubMed] [Google Scholar]
  • 8.Chen Y, Li D, Liu H, Xu H, Zheng H, Qian F, Li W, Zhao C, Wang Z, Wang X. Notch-1 signaling facilitates survivin expression in human non-small cell lung cancer cells. Cancer Biol Ther. 2011;11(1):14–21. doi: 10.4161/cbt.11.1.13730. [DOI] [PubMed] [Google Scholar]
  • 9.Eliasz S, Liang S, Chen Y, De Marco MA, Machek O, Skucha S, Miele L, Bocchetta M. Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway. Oncogene. 2010;27(17):2488–2498. doi: 10.1038/onc.2010.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991;66(4):649–661. doi: 10.1016/0092-8674(91)90111-b. [DOI] [PubMed] [Google Scholar]
  • 11.Rose SL, Kunnimalaiyaan M, Drenzek J, Seiler N. Notch 1 signaling is active in ovarian cancer. Gynecol Oncol. 2010;117(1):130–133. doi: 10.1016/j.ygyno.2009.12.003. [DOI] [PubMed] [Google Scholar]
  • 12.Restivo G, Nguyen BC, Dziunycz P, Ristorcelli E, Ryan RJ, Özuysal ÖY, Di Piazza M, Radtke F, Dixon MJ, Hofbauer GF, Lefort K, Dotto GP. IRF6 is a mediator of Notch pro-differentiation and tumor suppressive function in keratinocytes. EMBO J. 2011;30(22):4571–4585. doi: 10.1038/emboj.2011.325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Sriuranpong V, Borge MW, Ravi RK, Arnold DR, Nelkin BD, Baylin SB, Ball DW. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res. 2001;61(7):3200–3205. [PubMed] [Google Scholar]
  • 14.Shou J, Ross S, Koeppen H, de Sauvage FJ, Gao WQ. Dynamics of notch expression during murine prostate development and tumorigenesis. Cancer Res. 2001;61(19):7291–7297. [PubMed] [Google Scholar]
  • 15.Borges M, Linnoila RI, van de Velde HJ, Chen H, Nelkin BD, Mabry M, Baylin SB, Ball DW. An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature. 1997;386(6627):852. doi: 10.1038/386852a0. [DOI] [PubMed] [Google Scholar]
  • 16.Chu D, Zhang Z, Zhou Y, Wang W, Li Y, Zhang H, Dong G, Zhao Q, Ji G. Notch1 and Notch2 have opposite prognostic effects on patients with colorectal cancer. Ann Oncol. 2011;22:2440–2447. doi: 10.1093/annonc/mdq776. [DOI] [PubMed] [Google Scholar]
  • 17.Jaskula-Sztul R, Pisarnturakit P, Landowski M, Chen H, Kunnimalaiyaan M. Expression of the active Notch1 decreases MTC tumor growth in vivo. J Surg Res. 2011;171(1):23–27. doi: 10.1016/j.jss.2011.03.035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Xiao X, Ning L, Chen H. Notch1 mediates growth suppression of papillary and follicular thyroid cancer cells by histone deacetylase inhibitors. Mol Cancer Ther. 2009;8(2):350–356. doi: 10.1158/1535-7163.MCT-08-0585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Wells GA, Shea BJ, O’Connell D, Peterson J, Welch V, et al. The Newcastle–Ottawa scale (NOS) for assessing the quality of non-randomized studies in meta-analysis. Appl Eng Agric. 2012;18(6):727–734. [Google Scholar]
  • 20.Fu H, Ma C, Guan W, Cheng W, Feng F, Wang H. Expression of Notch 1 receptor associated with tumor aggressiveness in papillary thyroid carcinoma. Onco Targets Ther. 2016;9(1):1519–1523. doi: 10.2147/OTT.S98239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Park HS, Jung CK, Lee SH, Chae BJ, Lim DJ, Park WC, Song BJ, Kim JS, Jung SS, Bae JS. Notch 1 receptor as a marker of lymph node metastases in papillary thyroid cancer. Cancer Sci. 2012;103(2):305–309. doi: 10.1111/j.1349-7006.2011.02161.x. [DOI] [PubMed] [Google Scholar]
  • 22.Zhang J, Wang Y, Li D, Jing S. Notch and TGF-β/Smad3 pathways are involved in the interaction between cancer cells and cancer-associated fibroblasts in papillary thyroid carcinoma. Tumor Biol. 2014;35(1):379–385. doi: 10.1007/s13277-013-1053-z. [DOI] [PubMed] [Google Scholar]
  • 23.Long Q, Zuo D, Wang H, Xiao-Tao L. Expression of RECγ, P53, NOTCH1 and BRAF gene in thyroid cancer and their clinical relevance. J East China Norm Univ Nat Sci. 2012;6:89–95. [Google Scholar]
  • 24.Jing-You M, Zhe-Xu C, Hua-Gen L, Fu-Qiang Y, Yan W, Hao S, Zhen L. Expression and clinical significance of notch-1 protein in papillary thyroid carcinoma tissues and cervical lymph node metastases. Chin J Bases Clin Gen Surg. 2017;1:70–73. [Google Scholar]
  • 25.Bolós V, Gregobessa J, Pompa J. Notch signaling in development and cancer. Endocr Rev. 2007;28(3):339–363. doi: 10.1210/er.2006-0046. [DOI] [PubMed] [Google Scholar]
  • 26.Stylianou S, Collu GM, Clarke RB, Brennan K. Aberrant activation of Notch signaling in human breast cancer. Cancer Res. 2006;66(3):1517–1525. doi: 10.1158/0008-5472.CAN-05-3054. [DOI] [PubMed] [Google Scholar]
  • 27.Santagata S, Demichelis F, Riva A, Varambally S, Hofer MD, Kutok JL, Kim R, Tang J, Montie JE, Chinnaiyan AM, Rubin MA, Aste JC. JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res. 2004;64(19):6854–6857. doi: 10.1158/0008-5472.CAN-04-2500. [DOI] [PubMed] [Google Scholar]
  • 28.Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269–271. doi: 10.1126/science.1102160. [DOI] [PubMed] [Google Scholar]
  • 29.Zagouras P, Stifani S, Blaumueller CM, Carcangiu ML, Artavanis-Tsakonas S. Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci USA. 1995;92(14):6414–6418. doi: 10.1073/pnas.92.14.6414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Collins BJ, Kleeberger W, Ball DW. Notch in lung development and lung cancer. 2004;14(5):357–364. doi: 10.1016/j.semcancer.2004.04.015. [DOI] [PubMed] [Google Scholar]
  • 31.Purow BW, Haque RM, Noel MW, Su Q, Burdick MJ, Lee J, Sundaresan T, Pastorino S, Park JK, Mikolaenko I, Maric D, Eberhart CG, Fine HA. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 2005;65(6):2353–2363. doi: 10.1158/0008-5472.CAN-04-1890. [DOI] [PubMed] [Google Scholar]
  • 32.Gao J, Song Z, Chen Y, Xia L, Wang J, Fan R, Du R, Zhang F, Hong L, Song J, Zou X, Xu H, Zheng G, Liu J, Fan D. Deregulated expression of Notch receptors in human hepatocellular carcinoma. Dig Liver Dis. 2008;40(2):114–121. doi: 10.1016/j.dld.2007.08.001. [DOI] [PubMed] [Google Scholar]
  • 33.Hai L, Zhang C, Li T, Zhou X, Liu B, Li S, Zhu M, Lin Y, Yu S, Zhang K, Ren B, Ming H, Huang Y, Chen L, Zhao P, Zhou H, Jiang T, Yang X. Notch1 is a prognostic factor that is distinctly activated in the classical and proneural subtype of glioblastoma and that promotes glioma cell survival via the NF-κB (p65) pathway. Cell Death Dis. 2018;9(2):158. doi: 10.1038/s41419-017-0119-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Zhang Y, Li D, Feng F, An L, Hui F, Dang D, Zhao Q. Progressive and prognosis value of notch receptors and ligands in hepatocellular carcinoma: a systematic review and meta-analysis. Sci Rep. 2017;7(1):14809. doi: 10.1038/s41598-017-14897-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SL, Steward DL, Tuttle RM. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19(11):1167–1214. doi: 10.1089/thy.2009.0110. [DOI] [PubMed] [Google Scholar]
  • 36.Yamashita AS, Geraldo MV, Fuziwara CS, Kulcsar MA, Friguglietti CU, Costa RB, Baia GS, Kimura ET. Notch pathway is activated by MAPK signaling and influences papillary thyroid cancer proliferation. Transl Oncol. 2013;6(2):197–205. doi: 10.1593/tlo.12442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Zhang M, Qin Y, Zuo B, Gong W, Zhang S, Gong Y, Quan Z, Chu B. Overexpression of NOTCH-regulated Ankyrin Repeat Protein is associated with papillary thyroid carcinoma progression. PLoS ONE. 2017;12(2):e0167782. doi: 10.1371/journal.pone.0167782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A. SEER cancer statistics review, 1975–2009 (Vintage 2009 populations). NCI (2009).
  • 39.Yu J, Jiang H, Zhan R. Aberrant Notch signaling in glioblastoma stem cells contributes to tumor recurrence and invasion. Mol Med Rep. 2016;14(2):1263–1268. doi: 10.3892/mmr.2016.5391. [DOI] [PubMed] [Google Scholar]
  • 40.Wei-Ye D, Yan-Feng C, Zhu-Ming G, Hao L, Qiu-Li L, Yun-Fei G, Shu-Biao Y, Ze-Lei L. Expression of Notch-1 and recurrence-related factors in papillary thyroid carcinoma. Cancer Res Clinic. 2015;27(1):11–14. [Google Scholar]
  • 41.Mierke CT. The fundamental role of mechanical properties in the progression of cancer disease and inflammation. Rep Prog Phys. 2014;77(7):076602. doi: 10.1088/0034-4885/77/7/076602. [DOI] [PubMed] [Google Scholar]
  • 42.Saad S, Stanners SR, Yong R, Tang O, Pollock CA. Notch mediated epithelial to mesenchymal transformation is associated with increased expression of the Snail transcription factor. Int J Biochem Cell Biol. 2010;42(7):1115–1122. doi: 10.1016/j.biocel.2010.03.016. [DOI] [PubMed] [Google Scholar]
  • 43.Diaz B, Yuen A, Iizuka S, Higashiyama S, Courtneidge SA. Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia. J Cell Biol. 2013;201(2):279–292. doi: 10.1083/jcb.201209151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Li L, Zhao F, Lu J, Yang H, Wu C, Liu Y. Notch-1 signaling promotes the malignant features of human breast cancer through NF-κB activation. PLoS ONE. 2014;9(4):e95912. doi: 10.1371/journal.pone.0095912. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 45.Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH. Inhibition of nuclear factor κb activity by genistein is mediated via Notch-1 signaling pathway in pancreatic cancer cells. Int J Cancer. 2006;118(8):1930–1936. doi: 10.1002/ijc.21589. [DOI] [PubMed] [Google Scholar]
  • 46.Ito Y, Miyauchi A, Kobayash K, Kihara M, Miya A. Static and dynamic prognostic factors of papillary thyroid carcinoma. Endocr J. 2014;61(12):1145–1151. doi: 10.1507/endocrj.EJ14-0303. [DOI] [PubMed] [Google Scholar]

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