HOXA7 stimulates human hepatocellular carcinoma proliferation through cyclin E1/CDK2

Li,Yuehui; Yang,Xiao Hui; Fang,Shu Juang; Qin,Chang Fei; Sun,Rui Li; Liu,Zhao Yang; Jiang,Bin Yuan; Wu,Xiang; Li,Guancheng

doi:10.3892/or.2014.3668

HOXA7 stimulates human hepatocellular carcinoma proliferation through cyclin E1/CDK2

Authors:
- Yuehui Li
- Xiao Hui Yang
- Shu Juang Fang
- Chang Fei Qin
- Rui Li Sun
- Zhao Yang Liu
- Bin Yuan Jiang
- Xiang Wu
- Guancheng Li
View Affiliations

Affiliations: Tumor Immunobiology Laboratory of the Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Carcinogenesis, Ministry of Health, Central South University, Changsha, Hunan, P.R. China, Xiangya Third Hospital, Central South University, Changsha, Hunan, P.R. China
Published online on: December 11, 2014 https://doi.org/10.3892/or.2014.3668
Pages: 990-996

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

HOX genes are transcription factors that control morphogenesis, organogenesis and differentiation. Increasing evidence suggests that HOX genes play a role in hepatocellular carcinoma (HCC) progression; however few studies have defined the functional roles and mechanisms of action. In the present study, we used siRNA and forced-expression in multiple cell lines to define the role of HOXA7 in the regulation of proliferation of HCC in vitro and in vivo. Knockdown of endogenous HOXA7 decreased the proliferation of HepG2 and QGY-7703 cells. These changes were not associated with significant changes in cyclin D1 and CDK4. However, downregulation of HOXA7 significantly reduced cyclin E1 and CDK2 protein levels. Conversely, overexpression of HOXA7 in QSG-7701 cells stimulated proliferation and increased cyclin E1 and CDK2 protein levels. Our results confirmed that HOXA7 promoted cell proliferation, and these changes were mediated by cyclin E1/CDK2. These observations contribute to our understanding of the important roles of HOXA7 in HCC development and progression and HOXA7 could be a promising molecular target for the development of new diagnostic and therapeutic strategies for HCC.

View Figures

View References

1	Hao K, Luk JM, Lee NP, et al: Predicting prognosis in hepatocellular carcinoma after curative surgery with common clinicopathologic parameters. BMC Cancer. 9:3892009. View Article : Google Scholar : PubMed/NCBI
2	Song TJ, Ip EW and Fong Y: Hepatocellular carcinoma: current surgical management. Gastroenterology. 127(Suppl 1): S248–S260. 2004. View Article : Google Scholar : PubMed/NCBI
3	Paul SB, Gamanagatti SR, Mukund A, Abbas SZ and Acharya SK: Transarterial chemoembolization for hepatocellular carcinoma: significance of extrahepatic collateral supply. Indian J Cancer. 48:339–344. 2011. View Article : Google Scholar : PubMed/NCBI
4	Liu Y, Zhao Y, Fang S, Li Y and Li G: Molecular cloning and alternative splicing analysis of hepatoma associated gene HTA. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 38:869–875. 2013.(In Chinese). PubMed/NCBI
5	Liu Y, Li Y, Guo F, et al: Identification of HTA as a novel-specific marker for human hepatocellular carcinoma. J Cancer Res Clin Oncol. 136:1187–1192. 2010. View Article : Google Scholar : PubMed/NCBI
6	Liu Y, Zhao Y, Ju Q, et al: Molecular clone and functional study of a novel hepatoma associated gene. Int J Oncol. 42:1105–1112. 2013.PubMed/NCBI
7	Scott MP: A rational nomenclature for vertebrate homeobox (HOX) genes. Nucleic Acids Res. 21:1687–1688. 1993. View Article : Google Scholar : PubMed/NCBI
8	Kawazoe Y, Sekimoto T, Araki M, Takagi K, Araki K and Yamamura K: Region-specific gastrointestinal Hox code during murine embryonal gut development. Dev Growth Differ. 44:77–84. 2002. View Article : Google Scholar : PubMed/NCBI
9	Abate-Shen C: Deregulated homeobox gene expression in cancer: cause or consequence? Nat Rev Cancer. 2:777–785. 2002. View Article : Google Scholar : PubMed/NCBI
10	Samuel S and Naora H: Homeobox gene expression in cancer: insights from developmental regulation and deregulation. Eur J Cancer. 41:2428–2437. 2005. View Article : Google Scholar : PubMed/NCBI
11	Argiropoulos B and Humphries RK: Hox genes in hematopoiesis and leukemogenesis. Oncogene. 26:6766–6776. 2007. View Article : Google Scholar : PubMed/NCBI
12	Kanai M, Hamada J, Takada M, et al: Aberrant expressions of HOX genes in colorectal and hepatocellular carcinomas. Oncol Rep. 23:843–851. 2010.PubMed/NCBI
13	Cillo C, Schiavo G, Cantile M, et al: The HOX gene network in hepatocellular carcinoma. Int J Cancer. 129:2577–2587. 2011. View Article : Google Scholar : PubMed/NCBI
14	Boyault S, Rickman DS, de Reynies A, et al: Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 45:42–52. 2007. View Article : Google Scholar
15	Zhang X, Zhu T, Chen Y, Mertani HC, Lee KO and Lobie PE: Human growth hormone-regulated HOXA1 is a human mammary epithelial oncogene. J Biol Chem. 278:7580–7590. 2003. View Article : Google Scholar
16	Zhai Y, Kuick R, Nan B, et al: Gene expression analysis of preinvasive and invasive cervical squamous cell carcinomas identifies HOXC10 as a key mediator of invasion. Cancer Res. 67:10163–10172. 2007. View Article : Google Scholar : PubMed/NCBI
17	Naora H, Yang YQ, Montz FJ, Seidman JD, Kurman RJ and Roden RB: A serologically identified tumor antigen encoded by a homeobox gene promotes growth of ovarian epithelial cells. Proc Natl Acad Sci USA. 98:4060–4065. 2001. View Article : Google Scholar : PubMed/NCBI
18	Yamashita T, Tazawa S, Yawei Z, et al: Suppression of invasive characteristics by antisense introduction of overexpressed HOX genes in ovarian cancer cells. Int J Oncol. 28:931–938. 2006.PubMed/NCBI
19	Hamada J, Omatsu T, Okada F, et al: Overexpression of homeobox gene HOXD3 induces coordinate expression of metastasis-related genes in human lung cancer cells. Int J Cancer. 93:516–525. 2001. View Article : Google Scholar
20	Miyazaki YJ, Hamada J, Tada M, et al: HOXD3 enhances motility and invasiveness through the TGF-β-dependent and -independent pathways in A549 cells. Oncogene. 21:798–808. 2002. View Article : Google Scholar : PubMed/NCBI
21	Ohta H, Hamada J, Tada M, et al: HOXD3-overexpression increases integrin αvβ3 expression and deprives E-cadherin while it enhances cell motility in A549 cells. Clin Exp Metastasis. 23:381–390. 2006. View Article : Google Scholar
22	Grier DG, Thompson A, Kwasniewska A, McGonigle GJ, Halliday HL and Lappin TR: The pathophysiology of HOX genes and their role in cancer. J Pathol. 205:154–171. 2005. View Article : Google Scholar : PubMed/NCBI
23	Bhatlekar S, Fields JZ and Boman BM: HOX genes and their role in the development of human cancers. J Mol Med. 92:811–823. 2014. View Article : Google Scholar : PubMed/NCBI
24	Zhang Y, Huang Q, Cheng JC, et al: Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells. Reprod Biol Endocrinol. 8:612010. View Article : Google Scholar : PubMed/NCBI
25	Nunes FD, de Almeida FC, Tucci R and de Sousa SC: Homeobox genes: a molecular link between development and cancer. Pesqui Odontol Bras. 17:94–98. 2003. View Article : Google Scholar : PubMed/NCBI
26	Ota T, Choi KB, Gilks CB, Leung PC and Auersperg N: Cell type- and stage-specific changes in HOXA7 protein expression in human ovarian folliculogenesis: possible role of GDF-9. Differentiation. 74:1–10. 2006. View Article : Google Scholar : PubMed/NCBI
27	Ota T, Asahina H, Park SH, et al: HOX cofactors expression and regulation in the human ovary. Reprod Biol Endocrinol. 6:492008. View Article : Google Scholar : PubMed/NCBI
28	Hartwell LH and Weinert TA: Checkpoints: controls that ensure the order of cell cycle events. Science. 246:629–634. 1989. View Article : Google Scholar : PubMed/NCBI
29	Kamb A, Gruis NA, Weaver-Feldhaus J, et al: A cell cycle regulator potentially involved in genesis of many tumor types. Science. 264:436–440. 1994. View Article : Google Scholar : PubMed/NCBI
30	Pines J: Protein kinases and cell cycle control. Semin Cell Biol. 5:399–408. 1994. View Article : Google Scholar : PubMed/NCBI
31	Jung YJ, Lee KH, Choi DW, et al: Reciprocal expressions of cyclin E and cyclin D1 in hepatocellular carcinoma. Cancer Lett. 168:57–63. 2001. View Article : Google Scholar : PubMed/NCBI
32	Masaki T, Shiratori Y, Rengifo W, et al: Cyclins and cyclin-dependent kinases: comparative study of hepatocellular carcinoma versus cirrhosis. Hepatology. 37:534–543. 2003. View Article : Google Scholar : PubMed/NCBI
33	Dehay C and Kennedy H: Cell-cycle control and cortical development. Nat Rev Neurosci. 8:438–450. 2007. View Article : Google Scholar : PubMed/NCBI
34	van den Heuvel S and Harlow E: Distinct roles for cyclin-dependent kinases in cell cycle control. Science. 262:2050–2054. 1993. View Article : Google Scholar : PubMed/NCBI
35	Liu QX, Wang XF, Ikeo K, Hirose S, Gehring WJ and Gojobori T: Evolutionarily conserved transcription factor Apontic controls the G1/S progression by inducing cyclin E during eye development. Proc Natl Acad Sci USA. 111:9497–9502. 2014. View Article : Google Scholar : PubMed/NCBI
36	Gladden AB and Diehl JA: Cell cycle progression without cyclin E/CDK2: breaking down the walls of dogma. Cancer Cell. 4:160–162. 2003. View Article : Google Scholar : PubMed/NCBI
37	Rath SL and Senapati S: Why are the truncated cyclin Es more effective CDK2 activators than the full-length isoforms? Biochemistry. 53:4612–4624. 2014. View Article : Google Scholar : PubMed/NCBI