China special issue on gastrointestinal tumors-Improved survival after multidisciplinary team decision for patients with advanced gastrointestinal cancer: A multicenter, noninterventional, controlled study.

Formal multidisciplinary team (MDT) discussions in clinical practice require time and space but have unclear survival benefits for advanced gastrointestinal cancer patients. Our study aimed to investigate the long-term survival of patients with advanced gastrointestinal cancer after MDT decision. From June 2017 to June 2019, continuous MDT discussions on advanced gastrointestinal cancer were conducted in 13 medical centers in China. MDT decisions and actual treatment received by patients were prospectively recorded. The primary endpoint was the difference in overall survival (OS) between patients in the MDT decision implementation and nonimplementation groups. The secondary endpoints included the implementation rate of MDT decisions and subgroup survival analysis. A total of 461 MDT decisions of 455 patients were included in our study. The implementation rate of MDT decisions was 85.7%. Previous treatment had an impact on MDT decision-making. The OS was 24.0 months and 17.0 months in the implementation and nonimplementation groups, respectively. The implementation of MDT decisions significantly reduced the risk of death in multivariate analyses (hazard ratio = 0.518; 95% confidence interval: 0.304-0.884, P = .016). Subgroup analysis showed a significant difference in survival of patients with colorectal cancer, but not in survival of patients with gastric cancer. The rate of secondary MDT discussion was only 5.6% among patients who the MDT decisions were discontinued due to changes in their condition. MDT discussion can prolong the OS of patients with advanced gastrointestinal cancer, especially those with colorectal cancer. Timely scheduling of the subsequent MDT discussion is necessary when the disease condition changes.

Knockdown of KLF5 suppresses hypoxia-induced resistance to cisplatin in NSCLC cells by regulating HIF-1α-dependent glycolysis through inactivation of the PI3K/Akt/mTOR pathway.

BACKGROUND: Hypoxia-mediated chemoresistance has been regarded as an important obstacle in the development of cancer treatment. Knockdown of krüppel-like factor 5 (KLF5) was reported to inhibit hypoxia-induced cell survival and promote cell apoptosis in non-small cell lung cancer (NSCLC) cells via direct regulation of hypoxia inducible factor-1α (HIF-1α) expression. However, the roles of KLF5 in the development of hypoxia-induced cisplatin (DDP) resistance and its underlying mechanism in NSCLC cells remain to be further elucidated. METHODS: Western blot was performed to determine the protein levels of KLF5, P-glycoprotein (P-gp) and HIF-1α in treated NSCLC cells. Cell survival was examined by MTT assay. The effect of KLF5 knockdown on hypoxia-induced glycolysis was assessed by measuring glucose consumption and lactate production. The effect of KLF5 knockdown on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway was analyzed by western blot. RESULTS: Hypoxia upregulated the expression of KLF5 in NSCLC cells. KLF5 knockdown suppressed hypoxia-induced DDP resistance in NSCLC cells, as demonstrated by the increased cytotoxic effects of DDP and reduced P-gp expression in NSCLC cells in hypoxia. Moreover, KLF5 knockdown inhibited hypoxia-induced HIF-1α expression and glycolysis, and KLF5 knockdown suppressed hypoxia-induced DDP resistance by inhibiting HIF-1α-dependent glycolysis in NSCLC cells. Furthermore, KLF5 knockdown suppressed hypoxia-induced activation of the PI3K/Akt/mTOR pathway in NSCLC cells and KLF5 overexpression promoted hypoxia-induced DDP resistance in NSCLC cells through activation of the PI3K/Akt/mTOR pathway. CONCLUSIONS: KLF5 knockdown could suppress hypoxia-induced DDP resistance, and its mechanism may be due to the inhibition of HIF-1α-dependent glycolysis via inactivation of the PI3K/Akt/mTOR pathway.

Ubiquitin-conjugating enzyme E2C regulates apoptosis-dependent tumor progression of non-small cell lung cancer via ERK pathway.

The oncogenic role of ubiquitin-conjugating enzyme E2C (UBE2C) had been identified in some types of human tumors, while the clinical and biological role of UBE2C in non-small cell lung cancer (NSCLC) is still elusive. Here, we have determined the specific role of UBE2C in NSCLC. Western blot and qRT-PCR were used for detecting the mRNA level and protein level of UBE2C in NSCLC samples and cell lines, respectively. Lentivirus product was used to conduct loss of function assay. qRT-PCR array was employed to detect potential downstream genes regulated by UBE2C. As the result, UBE2C mRNA level was approximately threefold overexpression in NSCLC tissues compared with normal tissues, while a sharp change was detected at protein level. Overexpression of UBE2C in lung cancer samples was correlated with advanced pathological stage. UBE2C regulated cell growth in an apoptosis-dependent way. PCR Array analysis revealed that UBE2C regulated the expression of genes associated with tumor growth, apoptosis, and angiogenesis. Furthermore, UBE2C could regulate phospho-ERK1/2 level but not STAT3, YAP, or AKT pathway, which was accompanied with the classic function of ERK pathway in cell growth and apoptosis. In conclusion, our results indicated UBE2C might be a novel therapeutic target in NSCLC.

An activated Notch1 signaling pathway inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma cell line EC9706.

Previous studies have demonstrated that Notch1 signaling pathway plays a major role in maintaining the balance of cell proliferation, differentiation and apoptosis, and is closely associated with tumorigenesis. However, roles of Notch1 signaling pathway in esophageal squamous cell carcinoma (ESCC), which is a common cause of mortality in China, remain poorly understood. Therefore, a novel strategy for seeking a rational molecular therapeutic target for ESCC is urgently needed. The purpose of this study is to examine the effect of the active Notch1 signaling pathway on the proliferation and apoptosis of ESCC cells and to investigate the underlying molecular mechanisms in carcinogenesis of the esophagus. The results revealed that a constitutively activated Notch1 signaling pathway was observed in ESCC cell line EC9706, through a pcNICD vector mediated expression system. Clearly, the activated Notch1 signaling pathway gave rise to proliferation suppression of the cells, accompanied with a cell cycle inhibition at the G0/G1 phase and apoptosis. In contrast to the expression of CDK2, cyclin D1 and cyclin E observed in EC9706 cells untreated and transfected with pcDNA3.1, there was a markedly decrease in the cells stably expressing Notch1 NICD. Up- and down-regulations of GSK3 beta and beta-catenin, respectively, indicated that Notch1 inhibited proliferation and induced apoptosis of EC9706 cells through Wnt-mediated signaling pathway. These findings suggest that Notch1 signaling pathway may participate in carcinogenesis of the esophagus.