Correction: ESRP1 is overexpressed in ovarian cancer and promotes switching from mesenchymal to epithelial phenotype in ovarian cancer cells.

Since publication of the original article, the authors have noticed that there were errors in the labelling of Figures 6D and 6E. The correct figure and its legend are reproduced here. The authors wish to apologise for any inconvenience caused.

ESRP1 is overexpressed in ovarian cancer and promotes switching from mesenchymal to epithelial phenotype in ovarian cancer cells.

This corrects the article DOI: 10.1038/oncsis.2017.87.

ESRP1 is overexpressed in ovarian cancer and promotes switching from mesenchymal to epithelial phenotype in ovarian cancer cells.

Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2), epithelial cell-specific regulators of alternative splicing, are downregulated during the epithelial-mesenchymal transition (EMT). These factors have roles in tumor progression and metastasis in some cancers; however, their expression and function in ovarian cancer (OC) remain unclear. We found that ESRP1 and ESRP2 mRNAs were expressed at higher levels in OC cells than in immortalized ovarian surface epithelial (IOSE) cells, and confirmed their overexpression in OC tissues at the protein level. The Cancer Genome Atlas (TCGA) data analysis revealed frequent gene amplification of ESRP1 in OC tissues; however, we detected no significant correlation between ESRP1 gene copy number and gene expression in OC cells. Importantly, expression of ESRP1 and ESRP2 was inversely correlated with DNA methylation in OC cells, and ESRP2 overexpression in OC tissues was significantly associated with DNA hypomethylation. Notably, survival analysis using TCGA data from 541 OC tissues revealed that high ESRP1 expression was significantly associated with shorter 5-year survival of patients. Ectopic ESRP1 expression in mesenchymal OC cells promoted cell proliferation but suppressed cell migration. Furthermore, we found that ESRP1 drives a switch from mesenchymal to epithelial phenotype characterized by reduced cell migration in association with induction of epithelial cell-specific variant of CD44 and ENAH. Taken together, our findings suggest that an epigenetic mechanism is involved in ESRP1 overexpression, and that ESRP1 has a role in OC progression.

The effect of PPARγ agonist on SGLT2 and glucagon expressions in alpha cells under hyperglycemia.

BACKGROUND: Although sodium glucose cotransporter 2 (SGLT2) inhibitors have many beneficial effects for type 2 diabetes, including decreased cardiovascular death, recent reports that they increased glucagon through SGLT2 inhibition raised some concern. Troglitazone, Peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, was reported to increase SGLT2 in renal proximal tubule cells, but its role on pancreatic alpha cells have not been reported. We investigated the effect of troglitazone on SGLT2 expression in alpha cells and subsequent glucagon regulation in hyperglycemia. METHODS: An Alpha TC1-6 cell line was cultured in control (5 mM) or hyperglycemia (HG, 15 mM) for 72 h. We applied troglitazone with or without PPARγ antagonist (GW9662 10 µM). To investigate the involvement of PI3K/Akt pathway, we applied troglitazone with or without Wortmanin. We measured sodium glucose transporter 2 (SGLT2) and glucagon (GCG) mRNA and protein expression. PPAR gamma, PI3K and Akt protein were also measured. RESULTS: Exposure of alpha TC cells to HG for 72 h increased glucagon mRNA and protein expression. HG decreased SGLT2 mRNA and protein expression. Troglitazone significantly reversed HG-induced reduction of SGLT2 expression and increase of glucagon secretion. PPARγ antagonist (GW9662 10 µM) decreased the expression of SGLT2 and increased glucagon as HG did. Hyperglycemia increased PI3K and pAkt expression in alpha cells. Wortmanin (PI3K inhibitor, 1 µM) reversed HG-induced SGLT2 decrease and glucagon increase. Troglitazone treatment decreased PI3K and pAkt expression in HG. CONCLUSION: In conclusion, PPARγ agonist, troglitazone improved glucose transport SGLT2 dysfunction and subsequent glucagon dysregulation in alpha cell under hyperglycemia. Those effects were through the involvement of PI3K/pAkt signaling pathway. This study may add one more reason for the ideal combination of PPARγ agonist and SGLT2 inhibitor in clinical practice.

Triiodothyronine induces proliferation of pancreatic ß-cells through the MAPK/ERK pathway.

BACKGROUND: 3,5,3'-Triiodothyronine (T3) has a stimulatory effect on cellular growth via thyroid hormone receptors (TRs) in several cell lines. TR expression in the pancreas suggests that pancreatic beta cell proliferation might be induced by T3. The purpose of this study was to demonstrate that T3 induces pancreatic beta cell proliferation through the mitogen activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway. METHODS: INS-1 cells were plated as a monolayer at densities of 4×104, cultured in RPMI 1,640 with 10% fetal bovine serum with 2-mercaptoethanol, respectively, in 6-well multiplates. After 48 h, they were exposed to 10-7 M T3 or to vehicle alone. Viable cells were harvested after 24, 48, and 72 h of continuous exposure. Cell proliferation and TRα1 and TRß1 expression were analyzed by flow-assisted cell sorting analysis, Ki-67 staining, and Western blotting. The p38 MAPK, ERK, and Akt pathways were analyzed by Western blotting. Beta cell function was evaluated by assaying insulin secretion. RESULTS: T3 enhanced INS-1 cell proliferation at a dose of 10-7 M in a time-dependent manner via the MAPK/ERK pathway and promoted insulin secretion. CONCLUSIONS: Our results demonstrate that MAPK/ERK pathway plays an important role in the T3 induced pancreatic beta cell proliferation.

Clinical significance of CD151 overexpression in subtypes of invasive breast cancer.

BACKGROUND: CD151 is a member of the tetraspanin family, which interacts with laminin-binding integrins and other tetraspanins. This protein is implicated in motility, invasion, and metastasis of cancer cells, but the prevalence of CD151 expression in subtypes of breast cancers and its influence on clinical outcome remains to be evaluated. METHODS AND RESULTS: The immunohistochemistry-based tissue microarray analysis showed that 127 (14.3%) cases overexpressed CD151 among 886 breast cancer patients. CD151 overexpression was found to be significantly associated with larger tumour size, higher nodal stage, advanced stage, absence of oestrogen receptor and progesterone receptor, and human epidermal growth factor receptor 2 overexpression. CD151 overexpression resulted in poorer overall survival (OS) (P<0.001) and disease-free survival (P=0.02), and stage II and III patients with CD151 overexpression demonstrated substantially poorer OS (P=0.0474 and 0.0169). In the five subtypes analyses, CD151 overexpression retained its adverse impact on OS in the Luminal A (P=0.0105) and quintuple-negative breast cancer (QNBC) subtypes, one subgroup of triple-negative breast cancer (P=0.0170). Multivariate analysis that included stage, subtype, and adjuvant chemotherapy showed that CD151 overexpression was independently associated with poor OS in invasive breast cancer. CONCLUSION: CD151 overexpression may be a potential molecular therapeutic target for breast cancer, especially in QNBC subtype and more advanced stages of breast cancer.

Sonoporation of the minicircle-VEGF(165) for wound healing of diabetic mice.

PURPOSE: The purpose of this study is to examine the efficiency of sonoporation with minicircle DNA for the skin wound healing in diabetic mice. METHODS: Minicircle DNA containing the human VEGF(165) was constructed and tested in vitro. Diabetes was induced in 2-week old male C57BL/6J mice via streptozotocin (STZ) injection. 6 mm circular skin wounds were made on the mice back. After the subcutaneous injection of the minicircle DNA at the edge of the wound, the mice were exposed to the ultrasound irradiation for the sonoporation. Wound areas were analyzed until the day 12. Blood perfusion and angiogenesis were evaluated using a laser Doppler imaging and CD31 immunostaining, respectively. Re-epithelialization was assessed by histochemical analysis using hematoxylin and eosin staining. RESULTS: Accelerated wound closure was observed in the mice receiving sonoporation of minicircle-VEGF(165), which corresponds to the markedly increased skin blood perfusion and CD31 expression. Histological analysis revealed that the minicircle treated wound tissues showed fully restored normal architectures as compared with the non-treated diabetic controls with the markedly edematous and chaotic morphologies. CONCLUSIONS: Ultrasound mediated gene therapy with the minicircle-VEGF(165) is effective for the healing of the skin wound of the diabetic mice.

Expression profile of tight junction protein claudin 3 and claudin 4 in ovarian serous adenocarcinoma with prognostic correlation.

Tight junction proteins claudin 3 (CLDN3) and claudin 4 (CLDN4) are frequently altered in several human cancers, including ovarian carcinomas. Here, we examined the gene expression of CLDN3 and CLDN4 in various tumors, including 19 normal ovaries and 47 ovarian carcinomas by analyzing Affymetrix HG-U133 array data. Furthermore, a total of 114 ovarian serous tumors, including 10 adenomas, 20 borderline tumors and 84 carcinomas, were analyzed immunohistochemically to confirm the expression of two proteins and we assessed the association of their expression with the clinicopathological characteristics and survival of the patients. The microarray experiment revealed CLDN3 and CLDN4 transcripts were significantly up-regulated by 5-fold or more in most subtypes of ovarian epithelial carcinomas while the immunohistochemical analyses indicated that each protein was expressed in 68 (81.0%) and 72 (85.7%) of 84 serous adenocarcinomas, respectively. Borderline serous tumors and adenomas showed significantly lower expression of these proteins than the adenocarcinomas. Kaplan-Meier survival analysis showed that serous adenocarcinoma patients with high CLDN3 expression had substantially shorter survival (P=0.027). Multivariate analysis demonstrated that CLDN3 overexpression is an independent negative prognostic factor. Our findings suggest that CLDN3 overexpression can be used as a prognostic indicator in ovarian serous carcinomas. Moreover, CLDN3 may be a promising target for antibody-based therapy of ovarian carcinomas.