Hsa‑microRNA‑101 suppresses migration and invasion by targeting Rac1 in thyroid cancer cells

Wang,Chenghai; Lu,Sijia; Jiang,Jixin; Jia,Xiaoqin; Dong,Xiaoyun; Bu,Ping

doi:10.3892/ol.2014.2361

Hsa‑microRNA‑101 suppresses migration and invasion by targeting Rac1 in thyroid cancer cells

Authors:
- Chenghai Wang
- Sijia Lu
- Jixin Jiang
- Xiaoqin Jia
- Xiaoyun Dong
- Ping Bu
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Affiliations: Department of Pathology, Medical College of Yangzhou University, Yangzhou, Jiangshu 225001, P.R. China, Department of Pathology, The Affiliated Jiangsu Subei Hospital, Yangzhou University, Yangzhou, Jiangshu 225001, P.R. China, Department of Chinese and Western Integrative Medicine, Medical College of Yangzhou University, Yangzhou, Jiangshu 225001, P.R. China
Published online on: July 18, 2014 https://doi.org/10.3892/ol.2014.2361
Pages: 1815-1821

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Abstract

MicroRNAs (miRNAs) are 22‑ to 25‑nucleotide non‑coding RNA molecules that function as negative regulators of gene expression. In previous years, increasing evidence has arisen implicating the involvement of miRNAs in carcinogenesis. In previous studies, the role of miRNA‑101 (miR‑101) in tumors has been identified as a tumor suppressor and, until now, the role of miR‑101 and Rac1 in thyroid cancer has remained undefined. This study revealed that miR‑101 is significantly downregulated in papillary thyroid carcinoma (PTC) tissue and thyroid cancer cell lines, and that the downregulated miR‑101 is associated with lymph node metastasis. Infection with the miR‑101 murine stem cell virus may markedly inhibit cell migration and invasion in TPC‑1 and HTH83 thyroid cancer cell lines. Rac1 was demonstrated to be negatively regulated by miR‑101 at the post‑transcriptional level, via a specific target site within the 3' untranslated region by dual‑luciferase reporter assay. The expression of Rac1 was also observed to inversely correlate with miR‑101 expression in PTC tissues; knockdown of Rac1 by shRNA inhibited thyroid cancer cell migration and invasion, resembling that of miR‑101 overexpression. Thus, these findings suggested that miR‑101 acts as a novel suppressor by targeting the Rac1 gene and inhibiting thyroid cancer cell migration and invasion.

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1	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J cancer. 127:2893–2917. 2010.
2	Qian BY, Hem M, Dong SF, Wang JF and Chen KX: Incidence and mortality of thyroid cancers in Tianjin from 1981 to 2001. Zhonghua Nei Fen Mi Dai Xie Za Zhi. 5:432–434. 2005.(In Chinese).
3	Perri F, Lorenzo GD, Scarpati GD and Buonerba C: Anaplastic thyroid carcinoma: A comprehensive review of current and future therapeutic options. World J Clin Oncol. 2:150–157. 2011.
4	Hunt JP, Buchmann LO, Wang L and Abraham D: An analysis of factors predicting lateral cervical nodal metastases in papillary carcinoma of the thyroid. Arch Otolaryngol Head Neck Surg. 137:1141–1145. 2011.
5	Onoda N, Ishikawa T, Kawajiri H, Takashima T and Hirakawa K: Pattern of initial metastasis in the cervical lymph node from papillary thyroid carcinoma. Surg Today. 43:178–184. 2013.
6	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004.
7	Ambros V: The evolution of our thinking about microRNAs. Nat Med. 14:1036–1040. 2008.
8	Carthew RW and Sontheimer EJ: Origins and mechanisms of miRNAs and siRNAs. Cell. 136:642–655. 2009.
9	Wang HJ, Ruan HJ, He XJ, Ma YY, Jiang XT, Xia YJ, Ye ZY and Tao HQ: MicroRNA-101 is down-regulated in gastric cancer and involved in cell migration and invasion. Eur J Cancer. 46:2295–2303. 2010.
10	Su H, Yang JR, Xu T, Huang J, Xu L, Yuan Y and Zhuang SM: MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res. 69:1135–1142. 2009.
11	Li S, Fu H, Wang Y, Tie Y, Xing R, Zhu J, Sun Z, Wei L and Zheng X: MicroRNA-101 regulates expression of the v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) oncogene in human hepatocellular carcinoma. Hepatology. 49:1194–1202. 2009.
12	Wang R, Wang HB, Hao CJ, Cui Y, Han XC, Hu Y, Li FF, Xia HF and Ma X: MiR-101 is involved in human breast carcinogenesis by targeting Stathmin1. PLoS One. 7:e461732012.
13	Hao Y, Gu X, Zhao Y, Greene S, Sha W, Smoot DT, Califano J, Wu TC and Pang X: Enforced expression of miR-101 inhibits prostate cancer cell growth by modulating the COX-2 pathway in vivo. Cancer Prev Res (Phila). 4:1073–1083. 2011.
14	Hiroki E, Akahira J, Suzuki F, Nagase S, Ito K, Suzuki T, Sasano H and Yaegashi N: Changes in microRNA expression levels correlate with clinicopathological features and prognoses in endometrial serous adenocarcinomas. Cancer Sci. 101:241–249. 2010.
15	Zhang J, Socolovsky M, Gross AW and Lodish HF: Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system. Blood. 102:3938–3946. 2003.
16	He L and Hannon GJ: MicroRNAs small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004.
17	Didsbury J, Weber RF, Bokoch GM, Evans T and Snyderman R: rac, a novel ras-related family of proteins that are botulinum toxin substrates. J Biol Chem. 264:16378–16382. 1989.
18	del Pozo MA, Price LS, Alderson NB, Ren XD and Schwartz MA: Adhesion to the extracellular matrix regulates the coupling of the small GTPase Rac to its effector PAK. EMBO J. 19:2008–2014. 2000.
19	Chung CY, Lee S, Briscoe C, Ellsworth C and Firtel RA: Role of Rac in controlling the actin cytoskeleton and chemotaxis in motile cells. Proc Natl Acad Sci USA. 97:5225–5230. 2000.
20	Zhao SY, Sun Y, Lai ZS, Nan QZ, Li K and Zhang ZS: Inhibition of migration and invasion of colorectal cancer cells via deletion of Rac1 with RNA interference. Mol Cell Biochem. 322:179–184. 2009.
21	Chen QY, Xu LQ, Jiao DM, Yao QH, Wang YY, Hu HZ, Wu YQ, Song J, Yan J and Wu LJ: Silencing of Rac1 modifies lung cancer cell migration, invasion and actin cytoskeleton rearrangements and enhances chemosensitivity to antitumor drugs. Int J Mol Med. 28:769–776. 2011.
22	Zhen C, Chen L, Zhao Q, Liang B, Gu YX, Bai ZF, Wang K, Xu X, Han QY, Fang DF, et al: Gankyrin promotes breast cancer cell metastasis by regulating Rac1 activity. Oncogene. 32:3452–3460. 2013.
23	Hernández E, De La Mota-Peynado A, Dharmawardhane S and Vlaar CP: Novel inhibitors of Rac1 in metastatic breast cancer. P R Health Sci J. 29:348–356. 2010.
24	Kamai T, Shirataki H, Nakanishi K, Furuya N, Kambara T, Abe H, Oyama T and Yoshida K: Increased Rac1 activity and Pak1 overexpression are associated with lymphovascular invasion and lymph node metastasis of upper urinary tract cancer. BMC Cancer. 10:1642010.
25	Yap LF, Jenei V, Robinson CM, Moutasim K, Benn TM, Threadgold SP, Lopes V, Wei W, Thomas GJ and Paterson IC: Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation. Oncogene. 28:2524–2534. 2009.
26	Wang P, Chen L, Zhang J, Chen H, Fan J, Wang K, Luo J, Chen Z, Meng Z and Liu L: Methylation-mediated silencing of the miR-124 genes facilitates pancreatic cancer progression and metastasis by targeting Rac1. Oncogene. 23:514–524. 2014.
27	Imam JS, Plyler JR, Bansal H, Prajapati S, Bansal S, Rebeles J, Chen HI, Chang YF, Panneerdoss S, Zoghi B, et al: Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization. PLoS One. 7:e523972012.
28	Zhou Y, Su J, Shi L, Liao Q and Su Q: DADS downregulates the Rac1-ROCK1/PAK1-LIMK1-ADF/cofilin signaling pathway, inhibiting cell migration and invasion. Oncol Rep. 29:605–612. 2013.
29	Gupta GP and Massagué J: Cancer metastasis: building a framework. Cell. 127:679–695. 2006.
30	Klein CA: Cancer. The metastasis cascade. Science. 321:1785–1787. 2008.
31	Sreekumar R, Sayan BS, Mirnezami AH and Sayan AE: MicroRNA control of invasion and metastasis pathways. Front Genet. 2:582011.