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Loss of HSulf‐1 expression enhances tumorigenicity by inhibiting Bim expression in ovarian cancer
Author(s) -
He Xiaoping,
Khurana Ashwani,
Roy Debarshi,
Kaufmann Scott,
Shridhar Viji
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28818
Subject(s) - ectopic expression , ovarian cancer , gene knockdown , small hairpin rna , cancer research , downregulation and upregulation , biology , mapk/erk pathway , cancer , protein kinase b , cell culture , kinase , signal transduction , microbiology and biotechnology , gene , biochemistry , genetics
The expression of human Sulfatase1 (HSulf‐1) is downregulated in the majority of primary ovarian cancer tumors, but the functional consequence of this downregulation remains unclear. Using two different shRNAs (Sh1 and Sh2), HSulf‐1 expression was stably downregulated in ovarian cancer OV202 cells. We found that HSulf‐1‐deficient OV202 Sh1 and Sh2 cells formed colonies in soft agar. In contrast, nontargeting control (NTC) shRNA‐transduced OV202 cells did not form any colonies. Moreover, subcutaneous injection of OV202 HSulf‐1‐deficient cells resulted in tumor formation in nude mice, whereas OV202 NTC cells did not. Also, ectopic expression of HSulf‐1 in ovarian cancer SKOV3 cells significantly suppressed tumor growth in nude mice. Here, we show that HSulf‐1‐deficient OV202 cells have markedly decreased expression of proapoptotic Bim protein, which can be rescued by restoring HSulf‐1 expression in OV202 Sh1 cells. Enhanced expression of HSulf‐1 in HSulf‐1‐deficient SKOV3 cells resulted in increased Bim expression. Decreased Bim levels after loss of HSulf‐1 were due to increased p‐ERK, because inhibition of ERK activity with PD98059 resulted in increased Bim expression. However, treatment with a PI3 kinase/AKT inhibitor, LY294002, failed to show any change in Bim protein level. Importantly, rescuing Bim expression in HSulf‐1 knockdown cells significantly retarded tumor growth in nude mice. Collectively, these results suggest that loss of HSulf‐1 expression promotes tumorigenicity in ovarian cancer through regulating Bim expression.