No abstract

Abstract. The aim of the present study was to elucidate the effect of transmembrane protein 16A (TMEM16A) on portal vein smooth muscle cell (PVSMC) proliferation associated with portal vein remodeling in portal hypertension (PHT). Sprague-Dawley rats were subjected to bile duct ligation to establish a rat model of liver cirrhosis and PHT. Sham-operated animals served as controls. At 8 weeks after bile duct ligation, the extent of liver fibrosis and the portal vein wall thickness were assessed using hematoxylin-eosin staining. The protein expression levels of TMEM16A, extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2) in the portal vein were detected by immunohistochemistry and western blotting. In vitro, the lentivirus vectors were constructed and transfected into PVSMCs to upregulate the expression of TMEM16A. Isolated rat primary PVSMCs were treated with a small molecule inhibitor of TMEM16A, T16A-inhA01. Cell cycle was detected by flow cytometry. The activity of TMEM16A in the portal vein isolated from bile duct ligated rats was decreased, while the expression level of p-ERK1/2 was increased. However, in vitro, upregulation of TMEM16A promoted the proliferation PVSMCs, while inhibition of TMEM16A channels inhibited the proliferation of PVSMCs. The results indicated that TMEM16A contributes to PVSMCs proliferation in vitro, but in vivo, it may be a negative regulator of cell proliferation influenced by numerous factors.

MicroRNAs (miRNAs) are involved in the pathogenesis of intrahepatic cholangiocarcinoma (ICC). However, the role of microRNA-31 (miR-31) in ICC has yet to be elucidated. In this study, we demonstrated that the expression of miR-31 was significantly upregulated in ICC tissues and the human ICC cell line HCCC-9810, when compared with that in normal adjacent tissues. Bioinformatic analysis and a dual-luciferase reporter assay revealed RAS p21 GTPase activating protein 1 (RASA1) to be a direct target of miR-31 in HCCC-9810 cells. Further investigation showed that the protein expression level of RASA1 was significantly decreased in ICC tissues, suggesting an inverse correlation between miR-31 and RASA1 expression during the tumorigenesis of ICC. Moreover, the forced downregulation of miR-31 by its inhibitor in HCCC-9810 cells significantly inhibited cell proliferation and promoted cell apoptosis. However, when the cells were cotransfected with miR-31 inhibitor and RASA1-specific small interfering RNA (siRNA), these changes were attenuated. Further analysis of the molecular mechanism showed that the activity of the RAS-mitogen-activated protein kinase (MAPK) signaling pathway was significantly decreased in miR-31-downregulated HCCC-8910 cells, while cotransfection with miR-31 inhibitor and RASA1-specific siRNA attenuated this effect. These results indicate that the downregulation of RASA1 by miR-31 promoted cellular proliferation and inhibited cellular apoptosis, partially by upregulating the activity of the RAS-MAPK signaling pathway in ICC. In conclusion, the present study revealed important regulatory functions of miR-31 and RASA1 in ICC, indicating that miR-31 and RASA1 may become promising diagnostic and/or therapeutic targets for ICC.

Prohibitin-1 (PHB, also known as PHB1) is a pleiotropic protein in cells. PHB is a cell-surface receptor and is involved in the regulation of proliferation, apoptosis, transcription, and mitochondrial protein folding. PHB is upregulated in 5-8F cells, which overexpress LPLUNC1 (long palate, lung, nasal epithelium clone 1, a candidate tumour suppressor gene), and was identified using two-dimensional fluorescence difference gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF-MS/MS). Thus, we examined PHB mRNA levels using 24 nasopharyngeal carcinoma (NPC) and eight normal nasopharyngeal epithelium (NPE) tissues. Protein levels were detected using immunohistochemistry with a tissue microarray consisting of 323 NPC and NPE tissues. A Kaplan-Meier analysis was carried out, and the log-rank test was used to determine the statistical significance of the results using SPSS 15.0 software. PHB mRNA and protein expression levels were significantly downregulated in NPC tissue specimens compared with the NPE samples (P<0.01). In addition, decreased PHB expression correlates significantly with a poor prognosis, whereas decreased PHB protein expression is closely associated with advanced clinical stage and metastasis in NPC lesions. Therefore, we favour the hypothesis that the expression level of PHB could be used as a potential prognostic biomarker for NPC.

Gastric cancer is a gastrointestinal tumor with high morbidity and mortality rates. Several factors influence its progression, cell death being an important element. In this review, we summarized the effects of necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis, and eight less common cell death modalities on gastric cancer cells and the tumor microenvironment, detailed the molecular mechanisms of various cell death and their major regulatory pathways in gastric cancer, explored the prevalence and complexity of cell death in gastric cancer progression and highlighted the potentials of cell death-related therapies in gastric cancer.