LINC MIR503HG Controls SC-ß Cell Differentiation and Insulin Production by Targeting CDH1 and HES1.

Stem cell-derived pancreatic progenitors (SC-PPs), as an unlimited source of SC-derived ß (SC-ß) cells, offers a robust tool for diabetes treatment in stem cell-based transplantation, disease modeling, and drug screening. Whereas, PDX1+/NKX6.1+ PPs enhances the subsequent endocrine lineage specification and gives rise to glucose-responsive SC-ß cells in vivo and in vitro. To identify the regulators that promote induction efficiency and cellular function maturation, single-cell RNA-sequencing is performed to decipher the transcriptional landscape during PPs differentiation. The comprehensive evaluation of functionality demonstrated that manipulating LINC MIR503HG using CRISPR in PP cell fate decision can improve insulin synthesis and secretion in mature SC-ß cells, without effects on liver lineage specification. Importantly, transplantation of MIR503HG-/- SC-ß cells in recipients significantly restored blood glucose homeostasis, accompanied by serum C-peptide release and an increase in body weight. Mechanistically, by releasing CtBP1 occupying the CDH1 and HES1 promoters, the decrease in MIR503HG expression levels provided an excellent extracellular niche and appropriate Notch signaling activation for PPs following differentiation. Furthermore, this exhibited higher crucial transcription factors and mature epithelial markers in CDH1High expressed clusters. Altogether, these findings highlighted MIR503HG as an essential and exclusive PP cell fate specification regulator with promising therapeutic potential for patients with diabetes.

High GNG13 expression is associated with poor survival in epithelial ovarian cancer and breast cancer.

Recently, change in the GNG13 expression has been shown to result in multiple congenital malformations and sexual reversal, and it was also found in the brain. The aim of this study was to measure the expression levels in epithelial ovarian cancer (EOC) and breast cancer (BC) and assess their value as a potential prognostic marker. The correlation of GNG13 protein expression was detected by immunohistochemistry (IHC) in 119 EOC and 125 BC tissues. Assessment of the associations between GNG13 levels and various clinicopathological features was identified, the relationship between GNG13 and prognosis in BC and EOC patients was analyzed using online resources of Oncomine and Kaplan-Meier plotter. Protein expression levels of GNG13 were both significantly lower in BC and EOC compared with normal tissues (p<0.0001 and p<0.001, respectively). Among the clinicopathological characteristics of BC, tumor grade (p=0.001) and TNM stage (p=0.001) were significantly associated with low expression of GNG13. While in EOC, low expression of GNG13 was significantly related to FIGO stage (p=0.001), presence of metastasis (p=0.001), and CA125 (p=0.001). Our data suggest that GNG13 expression maybe as a new inhibitor, which can strongly inhibit metastasis and partially attenuates tumor growth in EOC and BC.

miR-573 suppresses pancreatic cancer cell proliferation, migration, and invasion through targeting TSPAN1.

PURPOSE: To explore whether miR-573 can suppress pancreatic cancer cell proliferation, migration, and invasion by targeting TSPAN1. METHODS: The expression of miR-573 and TSPAN1 in pancreatic cancer tissues and cells lines was analyzed using RT-qPCR. The human pancreatic cancer cell line PANC­1 was transfected with miR-573 mimic, pcDNA3.1-TSPAN1, or genOFFTM st-h-TSPAN1. The effects of miR-573 and TSPAN1 on cell proliferation, colony formation, migration, and invasion were analyzed by CCK­8, colony formation, transwell migration, and invasion assay, respectively. Target genes of miR-573 were screened using bioinformatics tools and confirmed by dual-luciferase reporter assay and real-time PCR. The effects of miR-573 in vivo were observed using tumor xenografts. RESULTS: We found that miR-573 is downregulated and TSPAN1 is upregulated in pancreatic cancer tissues and cells lines. Function assays demonstrated that overexpression of miR-573 inhibited cell proliferation, colony formation, migration, and invasion of pancreatic cancer cells, as well as suppressing tumor growth in vivo. Target genes of miR-573 were predicted using bioinformatics tools and confirmed by dual-luciferase reporter assay and RT-qPCR or western blotting. Downregulation of TSPAN1 also inhibited cell proliferation, colony formation, migration, and invasion of pancreatic cancer cells. Furthermore, overexpression of TSPAN1 attenuated miR-573-induced inhibition of pancreatic cancer cell proliferation and migration. CONCLUSION: Our findings indicated that miR-573 suppresses pancreatic cancer cell proliferation, migration, and invasion through targeting TSPAN1. TSPAN1 targeted by miR-573 might be a potential therapeutic target for clinical treatment of pancreatic cancer.

HAX-1 overexpression in gastric cancer promotes cell proliferation.

BACKGROUND: HAX-1 is involved in the regulation of cellular processes such as apoptosis, proliferation and migration and is closely related to tumorigenesis and tumor metastasis. However, expression of HAX-1 in gastric cancer and its role in tumor development and progression remain unclear. METHODS: Quantitative polymerase chain reaction was used to detect the expression of HAX-1 mRNA in gastric cancer tissues and adjacent non-tumorous tissues. Expression of HAX-1, caspase-3 and caspase-9 was detected by immunohistochemistry in gastric cancer. Small hairpin RNA (shRNA) plasmid was employed to establish SGC-7901 cell lines that expressed HAX-1 at low levels. The effect of HAX-1 expression on cell proliferation will be studied at the cell level. RESULTS: Quantitative polymerase chain reaction (qPCR) showed HAX-1 mRNA expression to be significantly upregulated in gastric cancer tissues. Based on immunohistochemical analysis, upregulation of HAX-1 protein expression correlates positively with the degree of tumor differentiation, vascular tumor thrombus, tumor-node-metastasis stage and lymph node metastatic status and negatively with expression of the apoptosis-related proteins caspase-3 and caspase-9. In addition, high HAX-1 protein expression indicates a poor prognosis. Serum starvation-release experiments revealed that HAX-1 promotes the proliferation of SGC-7901 gastric cancer cells; as cell proliferation increased, expression of HAX-1 also increased, whereas the expression levels of the apoptosis-related proteins caspase-3 and caspase-9 decreased. HAX-1 siRNA transfection experiments demonstrated that HAX-1 gene knockdown causes cell cycle arrest at the G0/G1 phase, inhibits proliferation, and downregulates HAX-1 expression while enhancing expression of apoptosis-related proteins. CONCLUSIONS: HAX-1 might exert its proliferation-promoting and anti-apoptotic effects by inhibiting expression of the apoptosis-related proteins caspase-3 and caspase-9.HAX-1 may be a potential target for the treatment of gastric cancer.