MUL1 identified as mitochondria-linked biomarker promoting cisplatin resistance in OC cells.

Ovarian cancer (OC) ranks among the prevalent tumors affecting the female reproductive system. The aim of this study was to evaluate mitochondria-associated platinum resistance genes using organoid models. Univariate Cox regression, LASSO and multivariate Cox regression analyses were performed on The Cancer Genome Atlas (TCGA) database to construct 2-gene prognostic signature (MUL1 and SSBP1), and GSE26712 dataset was used for external validation. In addition, the relationship between MUL1 and platinum resistance was examined by organoid culture, lentiviral transduction, CCK8 assay, and Western blot. The results showed that patients in the high-risk group exhibited significantly worse OS (P = 0.002, P = 0.017). Drug sensitivity analysis revealed that platinum resistance increased with the upregulation of MUL1 expression (Cor = 0.5154, P = 0.02). Our experimental findings demonstrated that knockout of the MUL1 gene significantly increased apoptosis and enhanced the sensitivity of the OC cell line A2780 to cisplatin. Through this study, we have provided strong evidence for further research on prognostic risk factors and individualized treatment in OC patients, and provided new insights into addressing platinum resistance in OC.

Clinicalpathologic and Prognostic Significance of CGI-58 in Endometrial Cancer.

Recent studies have reported that CGI-58 played an important role in carcinogenesis and tumoral progression in several cancers. In this study, we investigated the expression and prognostic value of CGI-58 in patients with endometrail cancer. Initially, the expression of CGI-58 was analyzed in 552 cases of endometrial carcinoma from The Cancer Genome Atlas (TCGA). Then, the mRNA level of CGI-58 from 32 normal endometrium and 40 endometrial cancer tissues was determined using real-time PCR. In addition, immunohistochemical staining of CGI-58 was performed in 140 endometrial specimens including 35 normal endometrial tissues, 25 atypical endometrial hyperplasia and 80 endometrial cancers. The expression of CGI-58 was significantly up-regulated in endometrial cancer tissues compared with normal endometrial tissue both in TCGA database and clinical cohorts. Over-expression of CGI-58 was significantly correlated with poor histological differentiation. Furthermore, high levels of CGI-58 expression were significantly associated with shorter overall survival for all analyzed cases. Our findings demonstrate that CGI-58 is up-regulated in endometrial cancer and high CGI-58 expression is a poor prognostic marker for endometrial cancer. CGI-58 may be a potential contributor to endometrial cancer oncogenesis and progression.

LINC00261 functions as a competing endogenous RNA to regulate BCL2L11 expression by sponging miR-132-3p in endometriosis.

Endometriosis is a benign disease but manifests with malignant features and limited treatment options. Women with endometriosis should not be ignored or patronized by the medical profession and society. In this regard, a major cultural change and searching for the optimum therapeutic regimen from multiple perspectives is needed in China even in the whole world. Long non-coding RNAs are crucial for various human diseases while its potential functions and mechanisms are largely unknown in endometriosis. LINC00261 was significantly downregulated in endometriosis tissues and our study indicated that it suppresses proliferation and invasion of endometriosis cells functionally in vitro. Insights of the mechanism of competitive endogenous RNAs were obtained from bioinformatic analysis, RIP, RNA pull-down and luciferase assays, which further confirmed that LINC00261 functions as a molecular sponge to regulate BCL2L11 expression by binding to miR-132-3p directly. These data defined LINC00261/miR-132-3p/BCL2L11 regulatory networks may be a novel therapeutic target for endometriosis.

Oncogenic role of ABHD5 in endometrial cancer.

BACKGROUND: Abhydrolase domain containing 5 (ABHD5) functions as a tumor suppressor in colorectal and prostate cancers. The aim of this study was to investigate the roles of ABHD5 in endometrial cancer. MATERIALS AND METHODS: ABHD5 expression was detected in clinical samples by immunohistochemical staining. Cell proliferation and invasion were evaluated with the Cell Counting Kit-8 and Transwell assay, respectively. Western blotting was performed to analyze protein expression. Glucose uptake was assessed by 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose. Lactate production was detected by a lactate assay kit. RESULTS: In the present study, ABHD5 was overexpressed in endometrial cancer tissues, and its expression was closely correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. In addition, we observed that the knockdown of ABHD5 inhibited cell proliferation, invasion, glucose uptake and lactate production in HEC-1A cells, which expressed high levels of ABHD5. Conversely, the opposite effects were observed when ABHD5 was ectopically expressed in Ishikawa cells, which had low levels of ABHD5. Furthermore, the changes in glycolysis regulators (enolase 1 [ENO1], glucose transporter 1 [GLUT1] and lactate dehydrogenase A [LDHA]) and epithelial-to-mesenchymal transition-related proteins (E-cadherin and Snail) in HEC-1A cells with ABHD5 knockdown were consistent with the effects of ABHD5 on glycolysis and cell invasion. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was increased, while the phosphorylated AKT (p-AKT) was decreased when ABHD5 was downregulated. Notably, treatment with the allosteric AKT inhibitor MK-2206 completely abolished the effects caused by ABHD5 overexpression in Ishikawa cells. Finally, ABHD5 knockdown potently suppressed tumor growth in vivo. CONCLUSION: Overall, these results suggest that ABHD5 may play an oncogenic role in endometrial cancer via the AKT pathway.

Upregulation of long noncoding RNA TUG1 by EGR1 promotes adenomyotic epithelial cell migration and invasion through recruiting EZH2 and suppressing TIMP2.

Emerging studies showed that lncRNA taurine upregulated 1 (TUG1) plays important roles in diverse biological processes. However, there is no previously published research reporting the regulatory role of lncRNAs in the progression of adenomyosis. In the present study, we found that TUG1 is upregulated in human adenomyosis, and the overexpression of TUG1 is associated with the transcription factor early growth response 1 (EGR1). Functionally, the knockdown of TUG1 inhibited adenomyotic epithelial cell migration and invasion but not growth. The mechanistic experiments demonstrated that the function of TUG1 in adenomyotic epithelial cell invasion is, at least in part, through recruiting the enhancer of zeste homolog 2 (EZH2) to the promoter of tissue inhibitor of metalloproteinases 2 (TIMP2) and negatively regulating its expression. Our study demonstrated that TUG1 promotes the migration and invasion of human adenomyotic epithelial cells, and EGR1/TUG1/EZH2/TIMP2 may be a potential therapeutic target for adenomyosis.

Decreased Expression of HOXA10 May Activate the Autophagic Process in Ovarian Endometriosis.

Autophagy is a survival process that maintains homeostasis in all eukaryotic cells. Recent studies show an abnormal autophagic activity in endometriosis, but the role of autophagy is controversial. Homeobox A10 (HOXA10) is a transcription factor necessary for embryonic and adult uterine development, and studies indicate that its expression decreases in endometriosis. Homeobox A10 may negatively regulate autophagy in endometriosis. To test this hypothesis, we measured the expression levels of autophagic biomarkers (beclin-1 and LC3-II) and HOXA10 proteins by Western blotting and messenger RNA (mRNA) by quantitative real-time polymerase chain reaction. Furthermore, we evaluated the serum cancer antigen 125 (CA125) levels by immunoassay. Most tested autophagic biomarker proteins and mRNAs were upregulated, whereas HOXA10 protein and mRNA were decreased in ovarian endometriomas compared with eutopic endometria of women with endometriosis and normal endometria. Compared with normal endometrium, only protein expression levels of autophagic biomarkers were increased in the eutopic endometrium of women with endometriosis. Moreover, HOXA10 was found to have a significant negative correlation with autophagy ( P < .01). Serum CA125 was at a high level in endometriosis and increased with elevated revised American Fertility Society staging (I-IV). There was a significant positive correlation between serum CA125 level and LC3-II protein level and/or LC3-II/LC3-I ratio ( P < .01) and a significant negative correlation between serum CA125 level and HOXA10 gene level ( P < .01). In conclusion, our studies support that the deficiency of HOXA10 may induce autophagy in endometriosis, and the relationship among CA125, autophagy, and HOXA10 in endometriosis requires additional research.

Long non-coding RNA LINC00261 inhibits cell growth and migration in endometriosis.

AIM: A previous study reported that LINC00261 is significantly downregulated in human ectopic endometrial tissues. The present study aimed to explore whether LINC00261 is functional in endometriosis cell proliferation, apoptosis and migration. METHODS: By transfecting human endometriosis cell line CRL-7566 with plasmids containing LINC00261, we successfully established the cell CRL-7566/LINC00261 with a high LINC00261 expression level. Cell-counting kit-8 and colony formation assays were conducted to evaluate the effect of LINC00261 on cell proliferation, and flow cytometry analysis and transwell migration assay were conducted to evaluate its effect on cell apoptosis and cell migration, respectively. RESULTS: Cell-counting kit-8 and colony formation assays both indicated that LINC00261 could inhibit cell proliferation in CRL-7566. Flow cytometry analysis confirmed that LINC00261 mediated inhibition of cell proliferation, which might be a consequence of inducting apoptosis. Furthermore, transwell migration assay indicated that LINC00261 could inhibit cell migration in endometriosis. CONCLUSION: LncRNA LINC00261 is capable of inhibiting cell growth and migration in endometriosis.