HOXD10 acts as a tumor-suppressive factor via inhibition of the RHOC/AKT/MAPK pathway in human cholangiocellular carcinoma

Yang,Haixia; Zhou,Jiupeng; Mi,Jianqiang; Ma,Ke; Fan,Yangwei; Ning,Jing; Wang,Chuying; Wei,Xin; Zhao,Huadong; Li,Enxiao

doi:10.3892/or.2015.4194

HOXD10 acts as a tumor-suppressive factor via inhibition of the RHOC/AKT/MAPK pathway in human cholangiocellular carcinoma

Authors:
- Haixia Yang
- Jiupeng Zhou
- Jianqiang Mi
- Ke Ma
- Yangwei Fan
- Jing Ning
- Chuying Wang
- Xin Wei
- Huadong Zhao
- Enxiao Li
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Affiliations: Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710062, P.R. China, Department of Medical Oncology, Xi'an Chest Hospital of Shaanxi, Xi'an, Shaanxi 710061, P.R. China, Department of Pathology, The First Affiliated Hospital of Henan Science and Technology University, Luoyang, Henan 471003, P.R. China, Department of General Surgery, Tangdu Hospital, Xi'an, Shaanxi 710038, P.R. China
Published online on: August 10, 2015 https://doi.org/10.3892/or.2015.4194
Pages: 1681-1691
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

HOXD10, a key regulator of cell-differentiated phenotype maintainence, has been demonstrated to be involved in the tumorigenesis of many human malignacies. However, the status of HOXD10 expression and its biological function in cholangiocellular carcinoma (CCC) remain to be clarified. In the present study, we investigated the clinical significance and biological functions of HOXD10 in CCC and found that the expression of HOXD10 and its downstream effector RHOC was significantly different in well-differentiated CCC tissues compared with poorly-differentiated lesions. We also observed a significant correlation between low HOXD10 and high RHOC expression levels and worse prognosis. The stable overexpression of HOXD10 by lentivirus vector significantly inhibited cell invasion partly by downregulating the expression of MMP2 and MMP9, and significantly increased early apoptosis in CCC cell lines and induced G1 phase cell cycle arrest, contributing to the inhibition of cell proliferation in vitro. Additionally, we demonstrated that the inactivation of the RHOC/AKT/MAPK pathway was involved in the tumor‑suppressive functions of HOXD10 in CCC. These results suggested that HOXD10 may be a putative suppressor gene and can act as a prognostic marker and potentially a novel therapeutic target for CCC.

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1	Lazaridis KN and Gores GJ: Cholangiocarcinoma. Gastroenterology. 128:1655–1667. 2005. View Article : Google Scholar : PubMed/NCBI
2	Mosconi S, Beretta GD, Labianca R, Zampino MG, Gatta G and Heinemann V: Cholangiocarcinoma. Crit Rev Oncol Hematol. 69:259–270. 2009. View Article : Google Scholar
3	Razumilava N and Gores GJ: Cholangiocarcinoma. Lancet. 383:2168–2179. 2014. View Article : Google Scholar : PubMed/NCBI
4	Cardinale V, Semeraro R, Torrice A, Gatto M, Napoli C, Bragazzi MC, Gentile R and Alvaro D: Intra-hepatic and extra-hepatic cholangiocarcinoma: New insight into epidemiology and risk factors. World J Gastrointest Oncol. 2:407–416. 2010. View Article : Google Scholar : PubMed/NCBI
5	Cillo C: HOX genes in human cancers. Invasion Metastasis. 14:38–49. 1994–1995.
6	Quinonez SC and Innis JW: Human HOX gene disorders. Mol Genet Metab. 111:4–15. 2014. View Article : Google Scholar
7	Shah N and Sukumar S: The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 10:361–371. 2010. View Article : Google Scholar : PubMed/NCBI
8	Carrio M, Arderiu G, Myers C and Boudreau NJ: Homeobox D10 induces phenotypic reversion of breast tumor cells in a three-dimensional culture model. Cancer Res. 65:7177–7185. 2005. View Article : Google Scholar : PubMed/NCBI
9	Wang YF, Li Z, Zhao XH, Zuo XM, Zhang Y, Xiao YH, Li J and Peng ZH: MicroRNA-10b is upregulated and has an invasive role in colorectal cancer through enhanced Rhoc expression. Oncol Rep. 33:1275–1283. 2015.PubMed/NCBI
10	Vardhini NV, Rao PJ, Murthy PB and Sudhakar G: HOXD10 expression in human breast cancer. Tumour Biol. 35:10855–10860. 2014. View Article : Google Scholar : PubMed/NCBI
11	Wang L, Chen S, Xue M, Zhong J, Wang X, Gan L, Lam EK, Liu X, Zhang J, Zhou T, et al: Homeobox D10 gene, a candidate tumor suppressor, is downregulated through promoter hypermethylation and associated with gastric carcinogenesis. Mol Med. 18:389–400. 2012.
12	Li Q, Ding C, Chen C, Zhang Z, Xiao H, Xie F, Lei L, Chen Y, Mao B, Jiang M, et al: miR-224 promotion of cell migration and invasion by targeting homeobox D 10 gene in human hepatocellular carcinoma. J Gastroenterol Hepatol. 29:835–842. 2014. View Article : Google Scholar
13	Nakayama I, Shibazaki M, Yashima-Abo A, Miura F, Sugiyama T, Masuda T and Maesawa C: Loss of HOXD10 expression induced by upregulation of miR-10b accelerates the migration and invasion activities of ovarian cancer cells. Int J Oncol. 43:63–71. 2013.PubMed/NCBI
14	Sasayama T, Nishihara M, Kondoh T, Hosoda K and Kohmura E: MicroRNA-10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC. Int J Cancer. 125:1407–1413. 2009. View Article : Google Scholar : PubMed/NCBI
15	Xiao H, Li H, Yu G, Xiao W, Hu J, Tang K, Zeng J, He W, Zeng G, Ye Z, et al: MicroRNA-10b promotes migration and invasion through KLF4 and HOXD10 in human bladder cancer. Oncol Rep. 31:1832–1838. 2014.PubMed/NCBI
16	Hakami F, Darda L, Stafford P, Woll P, Lambert DW and Hunter KD: The roles of HOXD10 in the development and progression of head and neck squamous cell carcinoma (HNSCC). Br J Cancer. 111:807–816. 2014. View Article : Google Scholar : PubMed/NCBI
17	Edge SBBD; Compton CC, Fritz AG, Greene FL and Trotti A: AJCC Cancer Staging Manual. 7th edition. Springer; New York: pp. 60–62. pp. 66–71. 2010
18	Ma L, Teruya-Feldstein J and Weinberg RA: Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 449:682–688. 2007. View Article : Google Scholar : PubMed/NCBI
19	Liu Z, Zhu J, Cao H, Ren H and Fang X: miR-10b promotes cell invasion through RhoC-AKT signaling pathway by targeting HOXD10 in gastric cancer. Int J Oncol. 40:1553–1560. 2012.PubMed/NCBI
20	Zhao ZH, Tian Y, Yang JP, Zhou J and Chen KS: RhoC, vascular endothelial growth factor and microvascular density in esophageal squamous cell carcinoma. World J Gastroenterol. 21:905–912. 2015.PubMed/NCBI
21	Gou WF, Zhao Y, Lu H, Yang XF, Xiu YL, Zhao S, Liu JM, Zhu ZT, Sun HZ, Liu YP, et al: The role of RhoC in epithelial-to-mesenchymal transition of ovarian carcinoma cells. BMC Cancer. 14:4772014. View Article : Google Scholar : PubMed/NCBI
22	Iiizumi M, Bandyopadhyay S, Pai SK, Watabe M, Hirota S, Hosobe S, Tsukada T, Miura K, Saito K, Furuta E, et al: RhoC promotes metastasis via activation of the Pyk2 pathway in prostate cancer. Cancer Res. 68:7613–7620. 2008. View Article : Google Scholar : PubMed/NCBI
23	Bu Q, Tang HM, Tan J, Hu X and Wang DW: Expression of RhoC and ROCK-1 and their effects on MAPK and Akt proteins in prostate carcinoma. Zhonghua Zhong Liu Za Zhi. 33:202–206. 2011.In Chinese. PubMed/NCBI
24	Islam M, Datta J, Lang JC and Teknos TN: Downregulation of RhoC by microRNA-138 results in de-activation of FAK, Src and Erk1/2 signaling pathway in head and neck squamous cell carcinoma. Oral Oncol. 50:448–456. 2014. View Article : Google Scholar : PubMed/NCBI
25	Mathema VB and Na-Bangchang K: Current insights on cholangiocarcinoma research: A brief review. Asian Pac J Cancer Prev. 16:1307–1313. 2015. View Article : Google Scholar : PubMed/NCBI
26	Ulahannan SV, Rahma OE, Duffy AG, Makarova-Rusher OV, Kurtoglu M, Liewehr DJ, Steinberg SM and Greten TF: Identification of active chemotherapy regimens in advanced biliary tract carcinoma: A review of chemotherapy trials in the past two decades. Hepat Oncol. 2:39–50. 2015. View Article : Google Scholar : PubMed/NCBI
27	Liao CG, Kong LM, Zhou P, Yang XL, Huang JG, Zhang HL and Lu N: miR-10b is overexpressed in hepatocellular carcinoma and promotes cell proliferation, migration and invasion through RhoC, uPAR and MMPs. J Transl Med. 12:2342014. View Article : Google Scholar : PubMed/NCBI
28	Redline RW, Hudock P, MacFee M and Patterson P: Expression of AbdB-type homeobox genes in human tumors. Lab Invest. 71:663–670. 1994.PubMed/NCBI
29	Ruth MC, Xu Y, Maxwell IH, Ahn NG, Norris DA and Shellman YG: RhoC promotes human melanoma invasion in a PI3K/Akt-dependent pathway. J Invest Dermatol. 126:862–868. 2006. View Article : Google Scholar : PubMed/NCBI
30	Ridley AJ: RhoA, RhoB and RhoC have different roles in cancer cell migration. J Microsc. 251:242–249. 2013. View Article : Google Scholar : PubMed/NCBI
31	Oxford G and Theodorescu D: Ras superfamily monomeric G proteins in carcinoma cell motility. Cancer Lett. 189:117–128. 2003. View Article : Google Scholar
32	Karlsson R, Pedersen ED, Wang Z and Brakebusch C: Rho GTPase function in tumorigenesis. Biochim Biophys Acta. 1796:91–98. 2009.PubMed/NCBI
33	Tumur Z, Katebzadeh S, Guerra C, Bhushan L, Alkam T and Henson BS: RhoC mediates epidermal growth factor-stimulated migration and invasion in head and neck squamous cell carcinoma. Neoplasia. 17:141–151. 2015. View Article : Google Scholar : PubMed/NCBI
34	Chen R, Cheng Y, Zhang Y, Li Z and Geng L: RhoC mediates invasion and migration of CaSki cells through the Rho-associated serine-threonine protein kinase 1 signaling pathway. Int J Gynecol Cancer. 24:184–191. 2014. View Article : Google Scholar : PubMed/NCBI
35	Bellovin DI, Simpson KJ, Danilov T, Maynard E, Rimm DL, Oettgen P and Mercurio AM: Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma. Oncogene. 25:6959–6967. 2006. View Article : Google Scholar : PubMed/NCBI
36	Wang W, Yang LY, Yang ZL, Peng JX and Yang JQ: Elevated expression of autocrine motility factor receptor correlates with overexpression of RhoC and indicates poor prognosis in hepato-cellular carcinoma. Dig Dis Sci. 52:770–775. 2007. View Article : Google Scholar : PubMed/NCBI
37	Maemura K, Natsugoe S and Takao S: Molecular mechanism of cholangiocarcinoma carcinogenesis. J Hepatobiliary Pancreat Sci. 21:754–760. 2014. View Article : Google Scholar : PubMed/NCBI
38	Dokduang H, Juntana S, Techasen A, Namwat N, Yongvanit P, Khuntikeo N, Riggins GJ and Loilome W: Survey of activated kinase proteins reveals potential targets for cholangiocarcinoma treatment. Tumour Biol. 34:3519–3528. 2013. View Article : Google Scholar : PubMed/NCBI
39	Leelawat K, Udomchaiprasertkul W, Narong S and Leelawat S: Induction of MKP-1 prevents the cytotoxic effects of PI3K inhibition in hilar cholangiocarcinoma cells. J Cancer Res Clin Oncol. 136:1537–1544. 2010. View Article : Google Scholar : PubMed/NCBI
40	Okada T, Sawada T and Kubota K: Rapamycin inhibits growth of cholangiocarcinoma cells. Hepatogastroenterology. 56:6–10. 2009.PubMed/NCBI
41	El-Khoueiry AB, Rankin CJ, Ben-Josef E, Lenz HJ, Gold PJ, Hamilton RD, Govindarajan R, Eng C and Blanke CD: SWOG 0514: A phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Invest New Drugs. 30:1646–1651. 2012. View Article : Google Scholar :
42	Ma L, Reinhardt F, Pan E, Soutschek J, Bhat B, Marcusson EG, Teruya-Feldstein J, Bell GW and Weinberg RA: Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nat Biotechnol. 28:341–347. 2010. View Article : Google Scholar : PubMed/NCBI
43	Zhang H, Cai K, Wang J, Wang X, Cheng K, Shi F, Jiang L, Zhang Y and Dou J: miR-7, inhibited indirectly by lincRNA HOTAIR, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway. Stem Cells. 32:2858–2868. 2014. View Article : Google Scholar : PubMed/NCBI