MicroRNA-92a-3p Enhances Cisplatin Resistance by Regulating Krüppel-Like Factor 4-Mediated Cell Apoptosis and Epithelial-to-Mesenchymal Transition in Cervical Cancer.

Recent studies have confirmed the existence and key roles of microRNA (miRNAs) in cancer drug resistance, including cervical cancer (CC). The present study aims to establish a novel role for miR-92a-3p and its associated gene networks in cisplatin (DDP) resistance of CC. First, the disparities in miRNA expression between CC tissues and adjacent normal tissues were screened based on GSE19611 microarray data that retrieved from Gene Expression Omnibus (GEO), and we identified several miRs that were significantly downregulated or upregulated in CC tissues including miR-92a-3p. Moreover, miR-92a-3p was significantly up-regulated in DDP-resistant cells and was the most differently expressed miRNA. Functionally, knockdown of miR-92a-3p increased the sensitivity of DDP-resistant cells to DDP via inhibiting cell proliferation, migration and invasion, and promoting apoptosis. Conversely, overexpression of miR-92a-3p significantly induced DDP resistance in CC parental cells including HeLa and SiHa cells. Moreover, Krüppel-like factor 4 (KLF4) was identified as a direct target of miR-92a-3p, and an obvious inverse correlation was observed between the expression of miR-92a-3p and KLF4 in 40 pairs of cancer tissues. Furthermore, KLF4 knockdown reversed the promoting effect of miR-92a-3p inhibition on DDP sensitivity in DDP-resistant CC cells. Besides, high expression of miR-92a-3p was associated with DDP resistance, as well as a short overall survival in clinic. Taken together, these findings provide important evidence that miR-92a-3p targets KLF4 and is significant in DDP resistance in CC, indicating that miR-92a-3p may be an attractive target to increase DDP sensitivity in clinical CC treatment.

Expression and clinical significance of long non-coding RNA HOTTIP in tissues of patients with endometrial carcinoma / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the expression and clinical significance of long non-coding RNA (lncRNA) HOTTIP in tissues of patients with endometrial carcinoma. Methods: A total of 109 cases of patients with endometrial carcinoma who underwent surgery in Xingxiang Central Hospital from April 2012 to April 2014 were selected. The endometrial carcinoma tissue and its corresponding adjacent tissue (more than 5 cm from the cancer margin) were obtained. The expressions of HOTTIP in endometrial carcinoma and adjacent tissues were detected by qRT-PCR. All patients were followed up from the first postoperative day. The follow-up deadline was April 30, 2019. The end-point event was death and the patient's survival time was recorded. Results: The relative expression level of HOTTIP in endometrial carcinoma tissues was (2.55±0.21), which was higher than that in the adjacent tissue (1.03±0.16) (t=60.631, P<0.01). The differences of the relative expression levels of HOTTIP in endometrial carcinoma tissues between different FIGO stage, histological grade, depth of myometrial invasion, lymphatic vascular infiltration status and lymph node metastasis were statistically significant (all P<0.05). Kaplan-Meier survival analysis showed that the 5-year survival rate and the survival time in the low expression group were higher than those in the high expression group [78.57% vs 37.04%, (70.67±4.94) months vs (42.14±3.65) months], the difference was statistically significant (χ2=12.839, P<0.01). Cox proportional hazards regression model analysis showed that the FIGO stage [HR=2.248 (95%CI: 1.034-4.887)], myometrial invasion depth [HR=3.055 (95%CI: 1.668-5.592)], lymph node metastasis [HR=3.811 (95%CI: 1.786-8.131)] and the expression of HOTTIP [HR=2.649 (95%CI: 1.026-6.842)] were all independent influence factors for the prognosis of patients with endometrial carcinoma. Conclusion: lncRNA HOTTIP is highly expressed in endometrial carcinoma tissues and associated with malignant progression of patients. It is an independent influencing factor for patients’ prognosis.

Expression and clinical significance of miR-191 in cervical cancer tissues / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the expression of miR-191 in cervical cancer tissues and its effect on the patients' prognosis. Methods: One hundred and seven cervical cancer tissue specimens from patients who underwent surgical treatment and 46 normal cervical tissue specimens from patients who underwent surgical resection of uterine fibroids (the control group) in Xinxiang Central Hospital were collected from December 2012 to December 2014. The expression of miR-191 in cancer tissues was detected by qPCR. All patients were followed up from the first day after surgery, and the follow-up deadline was December 31, 2019. All patients were followed up for 5 years, with death as the end event. The survival time and 5-year survival rate of the patients were recorded. Survival analysis was performed using Kaplan-Meier method and the factors affecting survival prognosis were analyzed using Cox proportional hazard regression model. Results: The expression level of miR-191 in cervical cancer tissues was significantly higher than that in the tissues from control group (P<0.01). There were significant differences in miR-191 expression among patients with different high-risk HPV infection status, different pathological grades and FIGO stages, and different lymph node metastasis status (all P<0.01). The 5-year survival rate of patients in the miR-191 low expression group was significantly higher than those patients in the high expression group (81.48% vs 33.75%, χ 2 =16.905, P<0.01). Pathological grade, FIGO stage, lymph node metastasis and the expression of miR-191 were risk factors affecting the prognosis of cervical cancer patients (HR=0.486, 3.065, 2.339 and 2.755, all P<0.05). Conclusion: miR-191 is highly expressed in cervical cancer tissues, and its expression level increases with the progression of malignancy. It is expected to become a potential biomarker for early diagnosis and prognosis evaluation of cervical cancer.

Long noncoding RNA opa-interacting protein 5 antisense transcript 1 promotes proliferation and invasion through elevating integrin α6 expression by sponging miR-143-3p in cervical cancer.

An increasing number of studies have shown that long noncoding RNAs (lncRNAs) play important roles in cervical cancer (CC) progression. However, the roles and underlying mechanisms of lncRNA opa-interacting protein 5 antisense transcript 1 (OIP5-AS1) involved in the CC remain unclear. In the current study, we found that lncRNA OIP5-AS1 was upregulated in CC tissues and cell lines. High OIP5-AS1 expression was significantly correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis, and poor overall survival of patients with CC. Using in vitro function assays, we showed that OIP5-AS1 suppression significantly decreased the proliferation, colony formation, and invasion ability of CC cells. Moreover, we revealed that OIP5-AS1 could act as a competing endogenous RNA of miR-143-3p to regulate the ITGA6 expression. Rescue assays showed that miR-143-3p inhibitors or ITGA6 overexpression could reverse the inhibitory effects of OIP5-AS1 suppression on the proliferation and invasion in CC cells. In addition, OIP5-AS1 suppression reduced tumor growth in vivo. In conclusion, we demonstrated that OIP5-AS1 promoted proliferation and invasion of CC cells via increasing the ITGA6 expression by sponging miR-143-3p, which might be an effective therapeutic target for the treatment of patients with CC.

MicroRNA-135a-3p is downregulated and serves as a tumour suppressor in ovarian cancer by targeting CCR2.

MicroRNAs have been demonstrated to play a crucial role in the development of ovarian cancer. Many studies prove that forms of miR-135a, including miR-135a-5p and miR-135a-3p, serve as tumour suppressors in multiple cancers. Nevertheless, the precise function of miR-135a-3p and the molecular mechanisms underlying the involvement of miR-135a-3p in ovarian carcinoma cell growth and metastasis remain largely unknown. Herein, we report that miR-135a-3p expression was significantly downregulated in ovarian carcinoma tissues compared with corresponding adjacent non-tumour tissues. Ectopic miR-135a-3p expression inhibited ovarian carcinoma cell proliferation, migration and invasion in vitro. Additionally, the overexpression of miR-135a-3p inhibited epithelial-mesenchymal transition (EMT) in ovarian cancer cells. A luciferase reporter assay confirmed that the C-C chemokine receptor type 2 (CCR2) gene was the target of miR-135a-3p. In addition, CCR2 depletion mimicked the inhibitory effects of miR-135a-3p on ovarian cancer cells in vitro. Rescue experiments using CCR2 overexpression further verified that CCR2 was a functional target of miR-135a-3p. Xenograft model assays demonstrated that miR-135a-3p functions as an anti-oncogene by targeting CCR2 in vivo. Taken together, these data prove that miR-135a-3p serves as a tumour suppressor gene in ovarian cancer by regulating CCR2.

Down-regulation of SIRT3 promotes ovarian carcinoma metastasis.

Distant metastasis and local recurrence are still the major causes for failure of treatment in patients with ovarian carcinoma (OC), making it urgent to further elicit the molecular mechanisms of OC metastasis. Sirtuin-3 (SIRT3), a member of the NAD(+)-dependent Class III histone deacetylases, may function as different role depending on the cell-type and tumor-type. However, the function and mechanism of SIRT3 has been not explored in OC metastasis. Here, we found that SIRT3 was significantly down-regulated in the metastatic tissues and highly metastatic cell line of ovarian cancer. In addition, knockdown of SIRT3 enhanced the migration and invasion in vitro and the liver metastasis in vivo of ovarian cancer cell. By contrast, ectopic overexpression of SIRT3 dramatically suppressed cancer cell metastatic capability. Mechanistically, SIRT3 inhibits epithelial-to-mesenchymal transition (EMT) by down-regulating Twist in ovarian cancer cells. Furthermore, an interaction between SIRT3 and Twist was detected. In conclusion, our results demonstrated that SIRT3 plays a crucial suppressive role in the metastasis of ovarian cancer by down-regulating Twist, and that this novel SIRT3/Twist axis may be valuable to develop new strategies for treating OC patients with metastasis.