SNHG22 overexpression indicates poor prognosis and induces chemotherapy resistance via the miR-2467/Gal-1 signaling pathway in epithelial ovarian carcinoma.

Recently, an increasing number of studies have reported that dysregulation of long noncoding RNAs (lncRNAs) plays an important role in cancer initiation and progression, including in epithelial ovarian carcinoma (EOC). However, little is known about the detailed biological functions of the lncRNA small nucleolar RNA host gene 22 (SNHG22) during the progression of EOC. Here, we found that SNHG22 was significantly increased in EOC tissues and was significantly associated with a low level of differentiation. Forced SNHG22 expression promoted chemotherapy resistance in EOC cells. Knockdown of SNHG22 expression increased the sensitivity of EOC cells to cisplatin and paclitaxel. Importantly, we found that SNHG22 could directly interact with miR-2467 and lead to the release of miR-2467-targeted Gal-1 mRNA. Moreover, SNHG22 overexpression induced EOC cell resistance to chemotherapy agents via PI3K/AKT and ERK cascade activation. In summary, our findings demonstrate that SNHG22 plays a critical role in the chemotherapy resistance of EOC by mediating the miR-2467/Gal-1 regulatory axis.

Elevated phosphatidylinositol 3-kinase activation and its clinicopathological significance in cervical cancer.

OBJECTIVE: The objective was to study the role of PI3K signaling in the development of cervical cancer and the antitumor effect of PI3K inhibitors. STUDY DESIGN: PI3K protein and mRNA expression of cervical cancer and non-neoplastic tissues were analyzed by Western blotting and RT-PCR. PI3K/Akt/mTOR pathway components in HeLa cells were assessed by immunocytochemistry and Western blotting. The inhibitive effect of LY294002 on HeLa cells was studied using MTT assay and flow cytometry. RESULTS: PI3K protein expression was detected in 25 out of 31 tumor specimens. Compared with non-neoplastic tissues, significant overexpression was observed in tumor tissues. For PI3K overexpression with all clinicopathological features, a decreasing trend in adenocarcinoma, advanced stage, and grade was observed. PI3K inhibitor LY294002 efficiently inhibited HeLa cell growth with IC50 of 20.77 microM, and induced apoptosis. The apoptotic rate was 36% at 3h after LY294002 treatment. These pharmacological roles of LY294002 might be played through the PI3K/Akt/mTOR signaling pathway. CONCLUSIONS: The PI3K signaling pathway was implicated in the development of cervical cancer. The activation of its signaling molecules might have clinical implications. Novel targeted therapies for the PI3K/Akt/mTOR signaling pathway components could provide a useful adjuvant therapeutic strategy for cervical cancer.

[Expression of phosphatidylinositol-3 kinase in epithelial ovarian carcinoma].

OBJECTIVE: To explore the expression and significance of phosphatidylinositol-3 kinase (PI3K) in ovarian cancer, and the effect of combined PI3K inhibitor (LY294002) therapy with cisplatin on epithelial ovarian carcinoma, and to explore if there is a synergistic effect between the two therapies. METHODS: The expression levels of PI3K p85 subunit proteins and mRNA were evaluated by western blot and RT-PCR in normal ovarian tissue (G1), ovarian benign tumor tissue (G2), ovarian borderline tumor tissue (G3) and ovarian cancer tissue (G4), and the relevant clinical pathological parameters were analyzed. SKOV3 cells were isolated and cultured by enzymolysis method. SKOV3 cells were treated with culture medium only, LY294002 (1, 10, 30, 50, 100 micromol/L), cisplatin (0.33, 1.25, 2.5, 5, 10 micromol/L), LY294002 (50 micromol/L) + cisplatin (10 micromol/L) for 2 days, respectively. The effect of LY294002 and cisplatin on the growth of SKOV3 cells was measured by methyl thiazolyl tetrazolium assay. RESULTS: There was no positive expression of PI3K p85 subunit proteins in G1 and G2, while the expression was 2/6 in G3, and 85% (33/39) in G4. PI3K p85 subunit mRNA expression levels were 0.178 +/- 0.102 in G1, 0.643 +/- 0.112 in G2, 0.847 +/- 0.058 in G3, 1.689 +/- 0.423 in G4; there was a significant difference between G1, G2, G3 and G4 (P<0.01). There was no significant correlation between protein expression and age at surgery or clinico-pathological staging (P>0.05). Significant differences were noted between protein expression levels in G4 (III, IV) and G4 (I, II; P<0.05). There was a significant difference between expression levels in tissues of different differentiation degrees (P<0.05). LY294002 and cisplatin inhibited the growth of SKOV3 cell in a concentration-dependent manner. The inhibitory activity of LY294002 at the concentration of 50 micromol/L was (46.0 +/- 2.0)% after treatment for two days. The inhibitory activity of cisplatin at the concentration of 10 micromol/L was (44.4 +/- 3.2)% after treatment for two days. After treatment for two days, the inhibitory activity of LY294002 50 micromol/L + cisplatin 10 micromol/L was (57.1 +/- 4.1)%. The inhibition effect on SKOV3 cell growth of the combined treatment group was better than the LY294002 or cisplatin treated group (P<0.01). CONCLUSIONS: PI3K p85 subunit is highly expressed and positively correlated with ovarian cancer. Different expression levels exist in tissues of late ovarian cancer, earlier ovarian cancer, borderline tumor, benign ovarian tumor and normal ovarian tissue. The changes in PI3K p85 subunit are correlated with tumor differentiation degree, but not pathologic typing. LY294002 combined with cisplatin can significantly enhance the killing efficiency in ovarian cancer cells.

Aberration of the PI3K/AKT/mTOR signaling in epithelial ovarian cancer and its implication in cisplatin-based chemotherapy.

OBJECTIVE: This study was to investigate the role of the PI3K/AKT/mTOR signaling in epithelial ovarian cancer development and its mechanism in cisplatin-based chemotherapy. STUDY DESIGN: Western blot and RT-PCR were used to determine the expression of PI3K-p85 subunit at protein and mRNA levels in normal and cancerous ovarian epithelium. SKOV3/DDP cells and SKOV3/MCA (multicellular aggregates) were constructed as chemo-resistant models. The role and mechanism of AKT specific inhibitor or shRNA in different models before and after cisplatin treatment were determined by multiple cellular and molecular approaches such as cell growth assay, flow cytometry, and western blot. RESULTS: PI3K-p85 subunit was detected in 33 out of 39 epithelial ovarian cancer specimens at protein level, but not detected in normal ovarian epithelium. A significant over-expression of PI3K-p85 subunit at mRNA level was observed in tumor tissues, and an increasing trend in advanced stage was also observed. Elevated activation of the AKT/mTOR/Survivin signaling was detected in SKOV3/DDP cells and SKOV3/MCA. Down-regulation of AKT by triciribine or shRNA transfection could attenuate cisplatin resistance through mTOR/Survivin signaling. CONCLUSIONS: The PI3K/AKT/mTOR signaling was involved in epithelial ovarian cancer development and cisplatin-based chemotherapy, and down-regulation of AKT could be an effective adjuvant antitumor therapy.