TRPC channels are Ca²⁺-permeable cationic channels controlling Ca²⁺ influx response to the activation of G protein-coupled receptors and protein tyrosine kinase pathways or the depletion of Ca²⁺ stores. Here we aimed to investigate whether TRPC can act as the potential therapeutic targets for ovarian cancer. The mRNAs of TRPC1, TRPC3, TRPC4 and TRPC6 were detected in human ovarian adenocarcinoma. The spliced variants of TRPC1β, TRPC3a, TRPC4β, TRPC4γ, and TRPC6 with exon 3 and 4 deletion were highly expressed in the ovarian cancer cells, and a novel spliced isoform of TRPC1 with exon 9 deletion (TRPC1(E9del)) was identified. TRPC proteins were also detected by Western blotting and immunostaining. The expression of TRPC1, TRPC3, TRPC4 and TRPC6 was significantly lower in the undifferentiated ovarian cancer cells, but all-trans retinoic acid up-regulated the gene expression of TRPCs. The expression level was correlated to the cancer differentiation grade. The non-selective TRPC channel blockers, 2-APB and SKF-96365, significantly inhibited the cell proliferation, whilst the increase of TRPC channel activity by trypsin promoted the cell proliferation. Transfection with siRNA targeting TRPC1, TRPC3, TRPC4 and TRPC6 or application of specific blocking antibodies targeting to TRPC channels inhibited the cell proliferation. On the contrary, overexpression of TRPC1, TRPC1(E9del), TRPC3, TRPC4, and TRPC6 increased the cancer cell colony growth. These results suggest that TRPCs and their spliced variants are important for human ovarian cancer development and alteration of the expression or activity of these channels could be a new strategy for anticancer therapy.

OBJECTIVEThe objectives of this study were to evaluate the rates of recurrence, survival and pregnancy, and characterize pregnancy outcomes of early-stage cervical cancer(eCC) treated with fertility-sparing methods such as cervical conization (CON) and radical trachelectomy(RT) with or without pelvic lymphadenectomy.STUDY DESIGNThis was a meta-analysis of observational studies analyzed by a random-effects model and a meta-regression to assess heterogeneity.RESULTSSixty observational studies encompassing 2,854 patients were included; 17 of which evaluated CON and 43 RT. Three hundred and seventy-five patients were included in the CON group: 176(46.9%) stage IA1 and 167(44.5%) stage IB1. In the RT group, 2479 cases were included: 143(6.0%) stage IA1, 299(12.1%) stage IA2, 1987(79.9%) stage IB1. CON was performed in 347(92.5%) cases, resulting in a recurrence rate of 0.4%(95%CI: 0.0%-1.4%), a death rate of 0%(0%-0%), a pregnancy rate of 36.1%(26.4%-46.2%), a spontaneous abortion rate of 14.8%(9.3%-21.2%) and a preterm delivery rate of 6.8%(1.5%-15.5%). For the RT group, 2273(91.7%) underwent successful surgeries with a recurrence rate of 2.3%(1.3%-3.4%),a death rate of 0.7%(0.3%-1.1%), a pregnancy rate of 20.5%(16.8%-24.5%), a spontaneous abortion rate of 24.0%(18.8%-29.6%) and a preterm delivery rate of 26.6%(19.6%-34.2%). From a subgroup analysis, the recurrence rates for stage IA tumors treated with CON and RT were 0.4%(0.0%-1.9%) and 0.7%(0.0%-2.3%), respectively; and for stage IB were 0.6%(0.0%-2.7%) and 2.3%(0.9%-4.1%).CONCLUSIONFertility-sparing treatment including CON or RT for eCC is feasible and carefully selected women can preserve fertility and achieve pregnancy resulting in live births. CON seems to result in better pregnancy outcomes than RT with similar rates of recurrence and mortality.

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Small extracellular vesicles (sEVs) are enriched in glycoconjugates and display specific glycosignatures. Aberrant expression of surface glycoconjugates is closely correlated with cancer progression and metastasis. The essential functions of glycoconjugates in sEVs are poorly understood. In this study, we observed significantly reduced levels of bisecting GlcNAc in breast cancer. Introduction of bisecting GlcNAc into breast cancer cells altered the bisecting GlcNAc status on sEVs, and sEVs with diverse bisecting GlcNAc showed differing functions on recipient cells. Carcinogenesis and metastasis of recipient cells were enhanced by sEVs with low bisecting GlcNAc, and the pro‐metastatic functions of sEVs was diminished by high bisecting GlcNAc modification. We further identified vesicular integrin β1 as a target protein bearing bisecting GlcNAc. Metastasis of recipient cells was strongly suppressed by high bisecting GlcNAc levels on vesicular β1. Our findings demonstrate the important roles of glycoconjugates on sEVs. Modification of sEV glycosylation may contribute to development of novel targets in breast cancer therapy.

Background PARP inhibitors have been the most promising target drugs with widely proven benefits among ovarian cancer patients. Although platinum-response, HR-related genes, or HRD genomic scar detection are acceptably used in assessment of Olaparib response, there are still evident limitations in the present approaches. Therefore, we aim to investigate more accurate approaches to predict Olaparib sensitivity and effective synergistic treatment strategies. Methods We probed two databases (TCGA and Qilu Hospital) in order to quest novel miRNAs associated with platinum-sensitivity or HR-related genes. Cellular experiments in vitro or in vivo and PDX models were utilized to validate their role in tumor suppression and Olaparib sensitizing. Furthermore, HR gene mutation was analyzed through WES to explore the relation between HR gene mutation and Olaparib response. Results High miR-509-3 expression indicated better response to platinum and longer progression-free and overall survival in two independent ovarian cancer patient cohorts (high vs. low miR-509-3 expression; PFS: TCGA P < 0.05, Qilu P < 0.05; OS: TCGA P < 0.05, Qilu P < 0.01). MiR-509-3 could impair the proliferation, migration, and invasion ability but enhance the sensitivity to Olaparib of ovarian cancer cell in vitro and in vivo by directly targeting HMGA2 and RAD51. In two PDX cases (PDX1 and PDX9), miR-509-3 could significantly increase the sensitivity to Olaparib along with the decrease of RAD51 positive rate (mean tumor weight NC + Olaparib vs. miR-509 + Olaparib; PDX1 P < 0.05, PDX9 P < 0.05). Additionally, in PDX8, miR-509-3 treatment dramatically reversed the Olaparib insensitivity (P < 0.05) by downregulating RAD51 expression. RAD51 functional detection revealed that all Olaparib sensitive cases exhibited low RAD51 positive rate (lesser than 50%) in treated groups. Furthermore, among the four HR gene mutation patients, three harbored HR core gene mutation and were sensitive to Olaparib while the remaining one with non-HR core gene mutation did not respond well to Olaparib. Conclusions MiR-509-3 can sensitize ovarian cancer cells to Olaparib by impeding HR, which makes it a potential target in PARPi synergistic treatment. HR core gene analysis and RAD51 functional detection are prospectively feasible in prediction of PARPi response.

Cyclooxygenase-2 (COX-2) expression is associated with many aspects of physiological and pathological conditions, including pancreatic beta-cell dysfunction. Prostaglandin E2 (PGE2) production, as a consequence of COX-2 gene induction, has been reported to impair beta-cell function. The molecular mechanisms involved in the regulation of COX-2 gene expression are not fully understood. In this report, we used pancreatic beta-cells (RINm5F) to explore the potential transcription factors regulating COX-2 promoter activity. Using promoter screening method, we selected several transcription factors in our study. Through luciferase reporter studies, we found that these factors can regulate COX-2 promoter activity in RINm5F cells. Among these factors, cyclic AMP response-element binding protein (CREB), Ets family members Ets-1 and Elk-1 can positively regulate COX-2 promoter activity. On the contrary, signal transducer and activator of transcription 1 (STAT1) plays a negative role on COX-2 promoter. Our findings will be helpful for better understanding the transcriptional regulation of COX-2 in pancreatic beta-cells. Moreover, these transcriptional regulators of COX-2 expression will be potential targets for the prevention of beta-cell damage mediated by PGE2.

The objective of this study was to illustrate the role of enhancer zeste homolog 2 (EZH2) overexpression in the proliferation, progression, and prognosis of cervical cancer. We detected EZH2 and Ki-67 expression levels using immunohistochemical (IHC) studies in 20 normal cervical tissues, 50 cervical intraepithelial neoplasia (including 25 low-grade intraepithelial lesions and 25 high-grade intraepithelial lesions), and 101 cervical cancer tissues. The relationships between EZH2 expression and Ki-67 expression, conventional clinicopathologic characteristics of cervical cancer, and patient outcomes were evaluated. The effect of EZH2 expression on cancer-specific survival was assessed by multivariate Cox regression analysis. Positive expression of EZH2 was detected in 10% (2/20) of the normal cervical tissues, 52% (13/25) of the low-grade squamous intraepithelial lesions, 64% (16/25) of the high-grade squamous intraepithelial lesions, and 68.3% (69/101) of the cervical cancer tissues. The expression of Ki-67 was positively correlated with EZH2 expression: 5% (1/20) in normal cervical tissues, 48% (12/25) in low-grade squamous intraepithelial lesions, 52% (13/25) in high-grade squamous intraepithelial lesions, and 57.4% (58/101) in cervical cancer tissues. Overexpression of EZH2 was adversely associated with clinical stage, histologic differentiation, infiltration depth, and lymph node metastasis (P<0.05). Patients with EZH2-positive expression showed a decreased overall survival compared with those with EZH2-negative expression (P=0.003, log-rank test). Multivariate Cox regression analysis suggested that overexpression of EZH2 was an independent predictor of poor prognosis in cervical cancer. Overexpression of EZH2 was closely associated with the carcinogenesis, proliferation, clinical and biologic behaviors, and the prognosis of cervical cancer, suggesting that it might be used as a potential predictor of prognosis in cervical cancer.

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