Interactions of Vascular Endothelial Growth Factor and p53 with miR-195 in Thyroid Carcinoma: Possible Therapeutic Targets in Aggressive Thyroid Cancers

Author(s): Hamidreza Maroof , Soussan Irani , Armin Arianna , Jelena Vider , Vinod Gopalan , Alfred King-yin Lam* .

Journal Name: Current Cancer Drug Targets

Volume 19 , Issue 7 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: The clinical pathological features, as well as the cellular mechanisms of miR-195, have not been investigated in thyroid carcinoma.

Objective: The aim of this study is to identify the interactions of vascular endothelial growth factor (VEGF), p53 and miR-195 in thyroid carcinoma. The clinical and pathological features of miR-195 were also investigated.

Methods: The expression levels of miR-195 were identified in 123 primary thyroid carcinomas, 40 lymph nodes with metastatic papillary thyroid carcinomas and seven non-neoplastic thyroid tissues (controls) as well as two thyroid carcinoma cell lines, B-CPAP (from metastasizing human papillary thyroid carcinoma) and MB-1 (from anaplastic thyroid carcinoma), by the real-time polymerase chain reaction. Using Western blot and immunofluorescence, the effects of exogenous miR-195 on VEGF-A and p53 protein expression levels were examined. Then, cell cycle and apoptosis assays were performed to evaluate the roles of miR-195 in cell cycle progression and apoptosis.

Results: The expression of miR-195 was downregulated in majority of the papillary thyroid carcinoma tissue as well as in cells. Introduction of exogenous miR-195 resulted in downregulation of VEGF-A and upregulation of p53 protein expressions. Upregulation of miR-195 in thyroid carcinoma cells resulted in cell cycle arrest. Moreover, we demonstrated that miR-195 inhibits cell cycle progression by induction of apoptosis in the thyroid carcinoma cells.

Conclusion: Our findings showed for the first time that miR-195 acts as a tumour suppressor and regulates cell cycle progression and apoptosis by targeting VEGF-A and p53 in thyroid carcinoma. The current study exhibited that miR-195 might represent a potential therapeutic target for patients with thyroid carcinomas having aggressive clinical behaviour.

Keywords: VEGF-A, p53, microRNA, miR-195, angiogenesis, thyroid carcinoma.

[1]
Lam, A.K.; Lo, C.Y.; Lam, K.S. Papillary carcinoma of thyroid: A 30-yr clinicopathological review of the histological variants. Endocr. Pathol., 2005, 16(4), 323-330.
[2]
Salajegheh, A.; Smith, R.A.; Kasem, K.; Gopalan, V.; Nassiri, M.R.; William, R.; Lam, A.K. Single nucleotide polymorphisms and mRNA expression of VEGF-A in papillary thyroid carcinoma: potential markers for aggressive phenotypes. Eur. J. Surg. Oncol., 2011, 37(1), 93-99.
[3]
Yu, X.M.; Lo, C.Y.; Lam, A.K.Y.; Leung, P.; Luk, J.M. Serum vascular endothelial growth factor C correlates with lymph node metastases and high-risk tumor profiles in papillary thyroid carcinoma. Ann. Surg., 2008, 247(3), 483-489.
[4]
Yu, X.M.; Lo, C.Y.; Lam, A.K.; Lang, B.H.; Leung, P.; Luk, J.M. The potential clinical relevance of serum vascular endothelial growth factor (VEGF) and VEGF-C in recurrent papillary thyroid carcinoma. Surgery, 2008, 144(6), 934-940.
[5]
Salajegheh, A.; Pakneshan, S.; Rahman, A.; Dolan-Evans, E.; Zhang, S.; Kwong, E.; Gopalan, V.; Lo, C.Y.; Smith, R.A.; Lam, A.K. Co-regulatory potential of vascular endothelial growth factor-A and vascular endothelial growth factor-C in thyroid carcinoma. Hum. Pathol., 2013, 44(10), 2204-2212.
[6]
Salajegheh, A.; Vosgha, H.; Rahman, M.A.; Amin, M.; Smith, R.A.; Lam, A.K. Interactive role of miR-126 on VEGF-A and progression of papillary and undifferentiated thyroid carcinoma. Hum. Pathol., 2016, 51, 75-85.
[7]
Ghahremani, M.F.; Goossens, S.; Nittner, D.; Bisteau, X.; Bartunkova, S.; Zwolinska, A.; Hulpiau, P.; Haigh, K.; Haenebalcke, L.; Drogat, B.; Jochemsen, A. p53 promotes VEGF expression and angiogenesis in the absence of an intact p21-Rb pathway. Cell Death Differ., 2013, 20(7), 888-897.
[8]
Farhang Ghahremani, M.; Goossens, S.; Haigh, J.J. The p53 family and VEGF regulation: “It’s complicated. Cell Cycle, 2013, 12(9), 1331-1332.
[9]
Mamoori, A.; Gopalan, V.; Lu, C.T.; Chua, T.C.; Morris, D.L.; Smith, R.A.; Lam, A.K. Expression pattern of miR-451 and its target MIF (macrophage migration inhibitory factor) in colorectal cancer. J. Clin. Pathol., 2017, 70(4), 308-312.
[10]
Lee, K.T.; Tan, J.K.; Lam, A.K.; Gan, S.Y. MicroRNAs serving as potential biomarkers and therapeutic targets in nasopharyngeal carcinoma: A critical review. Crit. Rev. Oncol. Hematol., 2016, 103, 1-9.
[11]
Ebrahimi, F.; Gopalan, V.; Wahab, R.; Lu, C.T.; Smith, R.A.; Lam, A.K. Deregulation of miR-126 expression in colorectal cancer pathogenesis and its clinical significance. Exp. Cell Res., 2015, 339(2), 333-341.
[12]
Salajegheh, A.; Vosgha, H.; Md Rahman, A.; Amin, M.; Smith, R.A.; Lam, A.K. Modulatory role of miR-205 in angiogenesis and progression of thyroid cancer. J. Mol. Endocrinol., 2015, 55(3), 183-196.
[13]
Chruscik, A.; Lam, A.K. Clinical pathological impacts of microRNAs in papillary thyroid carcinoma: A crucial review. Exp. Mol. Pathol., 2015, 99(3), 393-398.
[14]
Amin, M.; Lam, A.K. Current perspectives of mi-RNA in oesophageal adenocarcinoma: Roles in predicting carcinogenesis, progression and values in clinical management. Exp. Mol. Pathol., 2015, 98(3), 411-418.
[15]
Maroof, H.; Salajegheh, A.; Smith, R.A.; Lam, A.K. MicroRNA-34 family, mechanisms of action in cancer: a review. Curr. Cancer Drug Targets, 2014, 14(8), 737-751.
[16]
Vosgha, H.; Salajegheh, A.; Smith, R.A.; Lam, A.K. The important roles of miR-205 in normal physiology, cancers and as a potential therapeutic target. Curr. Cancer Drug Targets, 2014, 14(7), 621-637.
[17]
Maroof, H.; Salajegheh, A.; Smith, R.A.; Lam, A.K. Role of microRNA-34 family in cancer with particular reference to cancer angiogenesis. Exp. Mol. Pathol., 2014, 97(2), 298-304.
[18]
Ebrahimi, F.; Gopalan, V.; Smith, R.A.; Lam, A.K. miR-126 in human cancers: Clinical roles and current perspectives. Exp. Mol. Pathol., 2014, 96(1), 98-107.
[19]
Gopalan, V.; Pillai, S.; Ebrahimi, F.; Salajegheh, A.; Lam, T.C.; Le, T.K.; Langsford, N.; Ho, Y.H.; Smith, R.A.; Lam, A.K. Regulation of microRNA-1288 in colorectal cancer: altered expression and its clinicopathological significance. Mol. Carcinog., 2014, 53(Suppl. 1), E36-E44.
[20]
Flavin, R.J.; Smyth, P.C.; Laios, A.; O’Toole, S.A.; Barrett, C.; Finn, S.P.; Russell, S.; Ring, M.; Denning, K.M.; Li, J.; Aherne, S.T.; Sammarae, D.A.; Aziz, N.A.; Alhadi, A.; Sheppard, B.L.; Lao, K.; Sheils, O.M.; O’Leary, J.J. Potentially important microRNA cluster on chromosome 17p13.1 in primary peritoneal carcinoma. Mod. Pathol., 2009, 22(2), 197-205.
[21]
Xu, T.; Zhu, Y.; Xiong, Y.; Ge, Y.Y.; Yun, J.P.; Zhuang, S.M. MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells. Hepatology, 2009, 50(1), 113-121.
[22]
Yuen, P.W.; Chow, V.; Choy, J.; Lam, K.Y.; Ho, W.K.; Wei, W.I. The clinicopathologic significance of p53 and p21 expression in the surgical management of lingual squamous cell carcinoma. Am. J. Clin. Pathol., 2001, 116(2), 240-245.
[23]
Lam, A.K.; Ong, K.; Ho, Y.H. hTERT expression in colorectal adenocarcinoma: correlations with p21, p53 expressions and clinicopathological features. Int. J. Colorectal Dis., 2008, 23(6), 587-594.
[24]
Lam, K.Y.; Lo, C.Y.; Liu, M.C. Primary squamous cell carcinoma of the thyroid gland: an entity with aggressive clinical behaviour and distinctive cytokeratin expression profiles. Histopathology, 2001, 39(3), 279-286.
[25]
Chow, V.; Yuen, A.P.; Lam, K.Y.; Ho, W.K.; Wei, W.I. Prognostic significance of serum p53 protein and p53 antibody in patients with surgical treatment for head and neck squamous cell carcinoma. Head Neck, 2001, 23(4), 286-291.
[26]
Lam, K.Y.; Law, S.; Tin, L.; Tung, P.H.; Wong, J. The clinicopathological significance of p21 and p53 expression in esophageal squamous cell carcinoma: an analysis of 153 patients. Am. J. Gastroenterol., 1999, 94(8), 2060-2068.
[27]
Wang, M.; Zhang, J.; Tong, L.; Ma, X.; Qiu, X. MiR-195 is a key negative regulator of hepatocellular carcinoma metastasis by targeting FGF2 and VEGFA. Int. J. Clin. Exp. Pathol., 2015, 8(11), 14110-14120.
[28]
Wang, R.; Zhao, N.; Li, S.; Fang, J.H.; Chen, M.X.; Yang, J.; Jia, W.H.; Yuan, Y.; Zhuang, S.M. MicroRNA-195 suppresses angiogenesis and metastasis of hepatocellular carcinoma by inhibiting the expression of VEGF, VAV2, and CDC42. Hepatology, 2013, 58(2), 642-653.
[29]
Lam, A.K.Y. Pathology of endocrine tumors update: World health organization new classification 2017-other thyroid tumors. Am. J. Surg. Pathol. Rev. Rep, 2017, 22(4), 209-216.
[30]
Rosai, J.; Albores Saavedra, J.; Asiolis, S. In: Papillary thyroid carcinoma;; Lloyd, RV.; Osamura, RY.; Kloppel, G.; Rosai, J. WHO Classification of tumours of endocrine organs, International Agency for Research on Cancer: Lyon. , 2017, pp. (10)81-91.
[31]
Lloyd, R.V.; Erickson, L.A.; Casey, M.B.; Lam, K.Y.; Lohse, C.M.; Asa, S.L.; Chan, J.K.; DeLellis, R.A.; Harach, H.R.; Kakudo, K. LiVolsi, V.A.; Rosai, J.; Sebo, T.J.; Sobrinho-Simoes, M.; Wenig, B.M.; Lae, M.E. Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma. Am. J. Surg. Pathol., 2004, 28(10), 1336-1340.
[32]
Lang, B.H.; Lo, C.Y.; Chan, W.F.; Lam, A.K.; Wan, K.Y. Classical and follicular variant of papillary thyroid carcinoma: A comparative study on clinicopathologic features and long-term outcome. World J. Surg., 2006, 30(5), 752-758.
[33]
Smith, R.A.; Salajegheh, A.; Weinstein, S.; Nassiri, M.; Lam, A.K. Correlation between BRAF mutation and the clinicopathological parameters in papillary thyroid carcinoma with particular reference to follicular variant. Hum. Pathol., 2011, 42(4), 500-506.
[34]
Shi, X.; Liu, R.; Basolo, F.; Giannini, R.; Shen, X.; Teng, D.; Guan, H.; Shan, Z.; Teng, W.; Musholt, T.J.; Al-Kuraya, K.; Fugazzola, L.; Colombo, C.; Kebebew, E.; Jarzab, B.; Czarniecka, A.; Bendlova, B.; Sykorova, V.; Sobrinho-Simoes, M.; Soares, P.; Shong, Y.K.; Kim, T.Y.; Cheng, S.; Asa, S.L.; Viola, D.; Elisei, R.; Yip, L.; Mian, C.; Vianello, F.; Wang, Y.; Zhao, S.; Oler, G.; Cerutti, J.M.; Puxeddu, E.; Qu, S.; Wei, Q.; Xu, H.; O’Neill, C.J.; Sywak, M.S.; Clifton-Bligh, R.; Lam, A.K.; Riesco-Eizaguirre, G.; Santisteban, P.; Yu, H.; Tallini, G.; Holt, E.H.; Vasko, V.; Xing, M. Differential clinicopathological risk and prognosis of major papillary thyroid cancer variants. J. Clin. Endocrinol. Metab., 2016, 101(1), 264-274.
[35]
Michael, T.R.; Morris, L.F.; Haugen, B.R.; Shah, J.P.; Sosa, J.A.; Rohren, R.; Subramaniam, R.M.; Hurt, J.L.; Perrier, N.D. Thyroid-differentiated and anaplastic carcinoma. In: AJCC Cancer staging Manual; Amin, M.B.; Edge, S.; Greene, F.; Byrd, D.R.; Brookland, R.K.; Washington, M.K.; Gershenwald, J.E.; Compton, C.C.; Hess, K.R.; Sullivan, D.C.; Jessup, J.M.; Brierley, J.D.; Gaspar, L.E.; Schilsky, R.L.; Balch, C.M.; Winchester, D.P.; Asare, E.A.; Madera, M.; Gress, D.M.; Meyer, L.R; Springer: Berlin, 2016; Vol. 8, pp. 873-890.
[36]
Lam, K.Y.; Lo, C.Y.; Chan, K.W.; Wan, K.Y. Insular and anaplastic carcinoma of the thyroid: a 45-year comparative study at a single institution and a review of the significance of p53 and p21. Ann. Surg., 2000, 231(3), 329-338.
[37]
Wang, F.; Jiang, C.; Sun, Q.; Yan, F.; Wang, L.; Fu, Z.; Liu, T.; Hu, F. miR-195 is a key regulator of Raf1 in thyroid cancer. OncoTargets Ther., 2015, 20(8), 3021-3028.
[38]
Wang, R.; Zhao, N.; Li, S.; Fang, J.H.; Chen, M.X.; Yang, J.; Zhuang, S.M. MicroRNA-195 suppresses angiogenesis and metastasis of hepatocellular carcinoma by inhibiting the expression of VEGF, VAV2, and CDC42. Hepatology, 2013, 58(2), 642-653.
[39]
Fu, M.G.; Li, S.; Yu, T.T.; Qian, L.J.; Cao, R.S.; Zhu, H.; Xiao, B.; Jiao, C.H.; Tang, N.N.; Ma, J.J.; Hua, J.; Zhang, W.F.; Zhang, H.J.; Shi, R.H. Differential expression of miR195 in esophageal squamous cell carcinoma and miR-195 expression inhibits tumor cell proliferation and invasion by targeting of Cdc42. FEBS Lett., 2013, 587(21), 3471-349.
[40]
Heneghan, H.M.; Miller, N.; Kelly, R.; Newell, J.; Kerin, M.J. Systemic miRNA-195 differentiates breast cancer from other malignancies and is a potential biomarker for detecting noninvasive and early stage disease. Oncologist, 2010, 15(7), 673-682.
[41]
Wang, X.; Wang, J.; Ma, H.; Zhang, J.; Zhou, X. Downregulation of miR-195 correlates with lymph node metastasis and poor prognosis in colorectal cancer. Med. Oncol., 2012, 29(2), 919-927.
[42]
Jia, L.F.; Wei, S.B.; Gong, K.; Gan, Y.H.; Yu, G.Y. Prognostic implications of micoRNA miR-195 expression in human tongue squamous cell carcinoma. PLoS One, 2013, 8(2), e56634.
[43]
Fu, H.L.; Wu, D.P.; Wang, X.F.; Wang, J.G.; Jiao, F.; Song, L.L.; Xie, H.; Wen, X.Y.; Shan, H.S.; Du, Y.X.; Zhao, Y.P. Altered miRNA expression is associated with differentiation, invasion, and metastasis of esophageal squamous cell carcinoma (ESCC) in patients from Huaian, China. Cell Biochem. Biophys., 2013, 67(2), 657-668.
[44]
Wang, N.; Wei, H.; Yin, D.; Lu, Y.; Zhang, Y.; Zhang, Q.; Ma, X.; Zhang, S. MicroRNA-195 inhibits proliferation of cervical cancer cells by targeting cyclin D1a. Tumour Biol., 2016, 37(4), 4711-4720.
[45]
Sun, P.; Wang, L.; Lu, Y.; Liu, Y.; Li, L.; Yin, L.; Zhang, C.; Zhao, W.; Shen, B.; Xu, W. MicroRNA-195 targets VEGFR2 and has a tumor suppressive role in ACHN cells via PI3K/Akt and Raf/MEK/ERK signaling pathways. Int. J. Oncol., 2016, 49(3), 1155-1163.
[46]
Luo, Q.; Zhang, Z.; Dai, Z.; Basnet, S.; Li, S.; Xu, B.; Ge, H. Tumor-suppressive microRNA-195-5p regulates cell growth and inhibits cell cycle by targeting cyclin dependent kinase 8 in colon cancer. Am. J. Transl. Res., 2016, 8(5), 2088-2096.
[47]
Liu, C.D.; Wang, Q.; Zong, D.K.; Pei, S.C.; Yan, Y.; Yan, M.L.; Sun, L.L.; Hao, Y.Y.; Mao, M.; Xing, W.J.; Ren, H.; Ai, J. Knockdown of microRNA-195 contributes to protein phosphatase-2A inactivation in rats with chronic brain hypoperfusion. Neurobiol. Aging, 2016, 45, 76-87.
[48]
Shen, Y.H.; Xie, Z.B.; Yue, A.M.; Wei, Q.D.; Zhao, H.F.; Yin, H.D.; Mai, W.; Zhong, X.G.; Huang, S.R. Expression level of microRNA-195 in the serum of patients with gastric cancer and its relationship with the clinicopathological staging of the cancer. Eur. Rev. Med. Pharmacol. Sci., 2016, 20(7), 1283-1287.
[49]
Chen, D.; Li, M.; Luo, J.; Gu, W. Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function. J. Biol. Chem., 2003, 278(16), 13595-13598.
[50]
Yang, X.; Yu, J.; Yin, J.; Xiang, Q.; Tang, H.; Lei, X. MiR-195 regulates cell apoptosis of human hepatocellular carcinoma cells by targeting LATS2. Die Pharmazie, 2012, 67(7), 645-651.
[51]
Kumamoto, K.; Spillare, E.A.; Fujita, K.; Horikawa, I.; Yamashita, T.; Appella, E.; Nagashima, M.; Takenoshita, S.; Yokota, J.; Harris, C.C. Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence. Cancer Res., 2008, 68(9), 3193-3203.
[52]
Zetter, B.R. Angiogenesis and tumor metastasis. Annu. Rev. Med., 1998, 49, 407-424.
[53]
Zhang, Q.Q.; Xu, H.; Huang, M.B.; Ma, L.M.; Huang, Q.J.; Yao, Q.; Zhou, H.; Qu, L.H. MicroRNA-195 plays a tumor-suppressor role in human glioblastoma cells by targeting signaling pathways involved in cellular proliferation and invasion. Neuro-oncol., 2012, 14(3), 278-287.
[54]
Xu, L.; Huang, C.C.; Huang, W.; Tang, W.H.; Rait, A.; Yin, Y.Z.; Cruz, I.; Xiang, L.M.; Pirollo, K.F.; Chang, E.H. Systemic tumor-targeted gene delivery by anti-transferrin receptor scFv-immunoliposomes. Mol. Cancer Ther., 2002, 1(5), 337-346.
[55]
Xu, L.; Frederik, P.; Pirollo, K.F.; Tang, W.H.; Rait, A.; Xiang, L.M.; Huang, W.; Cruz, I.; Yin, Y.; Chang, E.H. Self-assembly of a virus-mimicking nanostructure system for efficient tumor-targeted gene delivery. Hum. Gene Ther., 2002, 13(3), 469-481.
[56]
Xu, L.; Pirollo, K.F.; Tang, W.H.; Rait, A.; Chang, E.H. Transferrin-liposome-mediated systemic p53 gene therapy in combination with radiation results in regression of human head and neck cancer xenografts. Hum. Gene Ther., 1999, 10(18), 2941-2952.
[57]
Arany, Z.; Foo, S.Y.; Ma, Y.; Ruas, J.L.; Bommi-Reddy, A.; Girnun, G.; Cooper, M.; Laznik, D.; Chinsomboon, J.; Rangwala, S.M.; Baek, K.H.; Rosenzweig, A.; Spiegelman, B.M. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature, 2008, 451(7181), 1008-1012.
[58]
Maroof, H.; Islam, F.; Ariana, A.; Gopalan, V.; Lam, A.K. The roles of microRNA-34b-5p in angiogenesis of thyroid carcinoma. Endocrine, 2017, 58(1), 153-166.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 7
Year: 2019
Page: [561 - 570]
Pages: 10
DOI: 10.2174/1568009618666180628154727
Price: $58

Article Metrics

PDF: 19
HTML: 2
EPUB: 1
PRC: 1