Suppression of tumorigenesis and metastasis of hepatocellular carcinoma by shRNA interference targeting on homeoprotein Six1

Kevin T.P. Ng, Kin Wah Lee, Qiao Cheng, Jana Y.H. Wo, Chris K.W. Sun, Dong Yong Guo, Zophia X. Lim, Chung Mau Lo, Ronnie T.P. Poon, Sheung Tat Fan, Kwan Man

Research output: Journal article publicationJournal articleAcademic researchpeer-review

34 Citations (Scopus)

Abstract

We previously demonstrated that the overexpression of homeoprotein Six1 in hepatocellular carcinoma (HCC) patients is associated with venous infiltration, advanced pathologic tumor metastasis (pTNM) stage and poor overall survival rate (Ng et al. Br J Cancer 2006;95:1050-5). In this study, short hairpin RNA (shRNA) interference approach was used to suppress the expression of Six1 in a metastatic HCC cell line MHCC97L. Stable transfectant MHCC97L-shSix1 carrying Six1-specific shRNA plasmid was established to downregulate Six1 expression to about 40% when compared with MHCC97L-Control. In vitro functional assays demonstrated that the growth rate and proliferation ability of MHCC97L-shSix1 cells were markedly decreased. Moreover, significant decrease of cell motility and invasiveness were observed in MHCC97L-shSix1 cells. Data from in vivo xenograft tumorigenesis model demonstrated that the size of tumor in MHCC97L-shSix1 group was dramatically reduced. Experimental and spontaneous metastasis models indicated that targeting Six1 suppression noticeably reduced the pulmonary metastasis in MHCC97L-shSix1 group. To identify Six1-regulated targets, cDNA microarray was employed to compare the expression profiles of MHCC97L-Control and MHCC97L-shSix1 cells. Twenty-eight downregulated and 24 upregulated genes with known functions were identified in MHCC97L-shSix1. The functions of these target genes are involved in diverse biological activities. Our data suggest that Six1 may be involved in regulation of proliferation and invasiveness of HCC; thus targeting suppression of Six1 is a viable option for treating HCC patients.
Original languageEnglish
Pages (from-to)859-872
Number of pages14
JournalInternational Journal of Cancer
Volume127
Issue number4
DOIs
Publication statusPublished - 15 Aug 2010
Externally publishedYes

Keywords

  • cDNA microarray
  • Hepatocellular carcinoma
  • Homeoprotein Six1
  • Interference
  • Metastasis
  • Short hairpin RNA (shRNA)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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