No abstract

Glucose-regulated protein 78 (GRP78), the most abundant and well-characterized glucose-regulated protein, is a major stress-inducible chaperone localized to the endoplasmic reticulum (ER). The purpose of the present study was to investigate the mechanisms of GRP78 involved in the senescence sensitivity of ovarian cancer cells to cisplatin. In the present study, we found that the chemotherapy-sensitive ovarian tumor sections showed strong staining for heterochromatin protein 1-γ (HP1-γ), but weak staining for GRP78. Cisplatin-sensitive A2780 cells with low expression of GRP78 tended to undergo senescence easily when compared with the cisplatin-resistant C13K cells following a dose-gradient cisplatin exposure. Forced overexpression of GRP78 protected the cisplatin-sensitive A2780 cells from cisplatin-induced senescence through P53 and CDC2. Knockdown of GRP78 rescued the senescence sensitivity of cisplatin-resistant C13K cells to cisplatin through P21 and CDC2. Twisting of Ca2+ release from ER stores by GRP78 was established to be associated with the sensitivity of cisplatin-induced senescence in ovarian cancer cell lines. In conclusion, GRP78 may have anti-senescence effects on ovarian cancer cells involving multiple mechanisms. Intervention against GRP78 may reduce cisplatin resistance in ovarian cancer.

Epithelial-to-mesenchymal transition (EMT) has been implicated as a dynamic cellular process in embryonic development and invasion of human cancers. Snail1 is a critical convergence hub in EMT regulation which transcriptionally represses E-cadherin expression. Currently, published data indicate that upregulation of Snail is mainly due to transcriptional activation and regulation of protein stability and cellular location. However, whether there is an alternative regulatory mechanism remains unclear. Our study showed that the expression of miR-153 was noticeably downregulated in hepatocellular carcinoma (HCC) cell lines and tissues, compared with normal liver epithelial cells (NLCs) and matched adjacent normal HCC tissues. Ectopic expression of miR-153 inhibited the migration and invasion ability of HCC cells, while suppression of miR-153 rescued this inhibitory effect. In addition, upregulation of miR-153 in HCC cells resulted in a decrease in epithelial markers, E-cadherin and α-catenin, and an increase in mesenchymal markers, N-cadherin and vimentin, and vice versa. Moreover, we demonstrated that miR-153 downregulated Snail expression by directly targeting the 3'-untranslated region (3'UTR) of Snail. Taken together, our results suggest that miR-153 plays a critical role in suppressing EMT and HCC progression by direct suppression of Snail expression.