No abstract

As a component of p53-dependent lncRNA (long non-coding RNA), PANDAR (the promoter of CDKN1A antisense DNA damage activated RNA) participates in the epigenetic regulation in human cancer. However, the involvement of PANDAR in cancer chemoresistance is unknown. In this study, we report that PANDAR serves as a negative regulator of cisplatin sensitivity in human ovarian cancer via PANDAR-SRFS2-p53 feedback regulation in nuclear. Our data showed that among the drugs commonly used in ovarian cancer therapy, cisplatin induces higher levels of PANDAR compared with doxorubicin and paclitaxel. We also proved that PANDAR exhibited higher expression in cisplatin-resistant ovarian cancer tissues and cells, compared with cisplatin-sensitive ones, and this expression pattern depends on wild-type p53 (wt-p53), not mutant-p53 (mt-p53). In vitro and in vivo, PANDAR overexpression improved cell survival rate and tumor growth in response to cisplatin, while depletion of PANDAR leads to a reduced tumor growth. Further investigation revealed that PANDAR-reduced cisplatin sensitivity was likely or partly due to the PANDAR-binding protein SFRS2 (arginine/serine-rich 2), a splicing factor with the ability to negative regulate p53 and its phosphorylation at Serine 15 (Ser15). This feedback regulation of PANDAR–SFRS2–p53 leads to a reduced transactivation of p53-related pro-apoptotic genes, such as PUMA (p53-upregulated modulator of apoptosis). In addition, in platinum-treated patients with relapsed ovarian cancer, resistant period was positively correlated with the expression of PANDAR and SFRS2, and inversely associated with expression of p53-Ser15 and PUMA in these clinical tissues. Last but not least, the role of PANDAR in chemoresistance was confirmed in patients with ovarian cancer. These findings reveal a novel regulatory maneuver of cancer cells in response to chemostress, and might shed light on overcoming cisplatin resistance in ovarian cancer.

The present study investigated the underlying role of growth arrest-specific transcript 5 (GAS5) in epithelial ovarian cancer (EOC), which is the main cause of death in women with malignant tumor of the genital system. In vivo GAS5 expression in 60 EOC specimens was evaluated by quantitative reverse transcription (qRT)-PCR, which was used to study the differences of GAS5 expression between EOC tissues and normal ovarian epithelium. In vitro GAS5 overexpression was applied to discover the biological functions in EOC cell lines. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide and colony formation assays were employed to investigate the effect on proliferation. The function of apoptosis was assessed by flow cytometry, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and JC-1 probe staining, and migration and invasion were detected by Transwell assay. The data show that no significant differences of GAS5 expression were observed between normal ovarian epithelium and benign epithelial lesions; however, GAS5 expression was lower in EOC tissues compared with normal ovarian epithelial tissues (6.44-fold), which was closely related to lymph node metastasis (P=0.025) and tumor node metastasis stage (P=0.035). Moreover, exogenous GAS5-inhibited proliferation promoted apoptosis and decreased migration and invasion in ovarian cancer cells. Finally, through mitochondrial potential and western blot analyses, GAS5 could disrupt mitochondrial membrane potential and promote BAX, BAK, cleaved-caspase 3 and cleaved-caspase 9 expression. Taken together, the findings of the present study revealed that GAS5 is downregulated in EOC specimens, and GAS5 inhibits EOC cell proliferation, migration and invasion, and promotes cell apoptosis. GAS5 can serve as a novel therapeutic target in patients with EOC.

Tannic acid (TA) has been associated with anticancer functions in multiple tumor types both in vitro and in vivo. However, its effect on ovarian carcinoma cells has not been investigated, and its underlying anticancer mechanism(s) remain unclear. In this study, the effects of TA alone and in combination with cisplatin were evaluated using ovarian carcinoma cell lines. Combined treatment with TA and cisplatin was found to induce apoptosis and increase DNA damage in the cisplatin-resistant (SKOV-3 CDDP/R) and cisplatin-sensitive (SKOV-3) human ovarian carcinoma cell lines, respectively. TA was also found to enhance the toxicity of cisplatin in ovarian carcinoma cells associated with the inhibition of poly(ADP-ribose) glycohydrolase (PARG) expression, increase the accumulation of poly(ADP-ribose) (pADPr), following the release of apoptosis-inducing factor, and the activation of caspase-3. In conclusion, as a PARG inhibitor, TA showed anticancer activity and increased the sensitivity of SKOV-3 cells and SKOV-3 CDDP/R cell lines to cisplatin.

Abstract. Long non-coding RNA colon cancer-associated transcript 2 (CCAT2) is dysregulated in a variety of types of human cancer. However, the role of CCAT2 in epithelial ovarian carcinoma (EOC) remains largely unknown. The aim of this study is to investigate the effect of CCAT2 on epithelial-mesenchymal transition (EMT) and related molecular mechanisms in epithelial ovarian cancer cells. In the current paper, we found that CCAT2 was significantly upregulated in EOC SKOV3, A2780 and HO8910 cell lines compared with the normal ovarian epithelial HUM-CELL-0088 cell line. Functional assays demonstrated that the knockdown of CCAT2 inhibited migration and invasion of EOC cells in vitro. Moreover, our results showed that silencing CCAT2 inhibited EMT by the upregulation of epithelial cadherin and downregulation of neural cadherin, zinc finger protein SNAI and Twist-related protein 1 in SKOV3 and A2780 cell lines. But, that was reversed by the treatment with lithium chloride (LiCl), by which the canonical Wnt/β-catenin pathway could be activated. In addition, we further investigated the role of CCAT2 in the modulation of Wnt/β-catenin signaling pathway. Our results revealed that knockdown of CCAT2 inhibited the expression of β-catenin and the activity of T-cell factor/lymphoid enhancer factor, acting as a key transcription factor of Wnt signaling pathway. Collectively, these results indicate that CCAT2 may promote EMT, at least partly through Wnt/β-catenin signaling pathway in EOC cells. Thus, CCAT2 might play a critical role in EOC progression and serve as a valuable target for the treatment of ovarian cancer.