Formyl peptide receptor 2 (FPR2), a classical chemoattractant receptor of G-protein-coupled receptors, is reported to be involved in invasion and metastasis of some cancers, but the role of FPR2 in gastric cancer (GC) has not yet been elucidated. In this study, we found that the levels of FPR2 expression in GC were positively correlated with invasion depth, lymph node metastasis and negatively correlated with the patients’ overall survival. Multivariate analysis indicated that FPR2 expression was an independent prognostic marker for GC patients. FPR2-knockdown significantly abrogated the migration and invasion stimulated by Hp(2–20) and Ac(2–26), two well-characterized ligands for FPR2 in GC cells. FPR2 deletion also reduced the tumorigenic and metastatic capabilities of GC cells in vivo. Mechanistically, stimulation with FPR2 ligands resulted in down-regulation of E-cadherin and up-regulation of vimentin, which were reversed by FPR2 knock-down, implying the involvement of epithelial–mesenchymal transition (EMT). Moreover, the activation of FPR2 was accompanied with ERK1/2 phosphorylation, which could be attenuated by FPR2 silencing or treatment with MEK inhibitor, PD98059. Altogether, our results demonstrate that FPR2 is functionally involved in invasion and metastasis, and potentially acts as a novel prognostic marker as well as a potential therapeutic target in human GC.

Currently, 5-Fluorouracil (5-FU) based chemotherapy is the primary option for colorectal cancer after surgery, whereas chemotherapy resistance related mortality is observed in a large proportion of patients. Anemoside B4 (AB4) is a triterpene saponin, which exhibits a considerable activity in oncotherapy. In this study, we explored the efficacy of AB4 in FU-based chemotherapy in colorectal cancer cells and the underlying molecular mechanisms. Our results indicated a significant synergistic activity of AB4 in 5-FU treated colorectal cancer cells. Furthermore, AB4 treatment eliminated colorectal cancer stem cells by promoting apoptotic cell death in 5-FU resistant colorectal cancer cells. Mechanically, AB4 activated caspase-9 pathway in 5-FU resistant colorectal cancer cells. Elevated Src activity induced cell apoptosis and cancer stem cells elimination effects in AB4 treated colorectal cancer cells. In conclusion, AB4 showed promising sensitization effect in the FU-based chemotherapy of colorectal cancer. Our study may pave a way to ameliorate FU-based chemotherapeutic efficiency in colorectal cancer.

Objective. To identify any concomitant complications other than bleeding (COTB) before and after endoscopic treatment of esophagogastric variceal bleeding (EGVB) in liver cirrhosis patients and explore the underlying risk factors. Materials and Methods. Cirrhotic patients complicated with EGVB, who underwent interventional endoscopic treatments in our hospital from November 2017 to August 2020, were enrolled in this study. Clinical data were retrospectively analyzed for COTB at admission and within 2 years of the first endoscopic treatment. Patients were screened for potential risk factors of COTB before and after the treatment. Univariate analysis was performed to identify clinical factors of secondary complications, and statistically significant factors were included in the multivariate Cox and logistic regression analyses. Results. Of the 547 patients with cirrhosis, 361 individuals had COTB in the first endoscopic treatment. In this cohort, the top 3 prevalent incidences were portal vein thrombosis (PVT) or spongiosis, cholelithiasis, and pathogenic infections. The COTB did not occur at admission in 171 liver cirrhosis patients but happened at the follow-up. Higher Child-Pugh scores indicated potential risks of multiple concurrent complications, including bleeding. Risk factors for concomitant PVT or cavernous changes after endoscopic treatment of EGVB, pathogenic infections, and cholelithiasis could prolong the cirrhosis symptoms, while noncholestatic cirrhosis patients might have a lower risk than posthepatitis B cirrhosis patients, in the context of a higher degree of EGV and serum level of D-D and a lower blood calcium level. Conclusions. Clinical treatment and interventions can be tailored to avoid other complications during and after EGVB treatment, which can affect the outcome and prognosis of bleeding symptoms.

KIT kinase V559D mutation is the most prevalent primary gain-of-function mutation in Gastrointestinal Stromal Tumors (GISTs). Here we reported a highly selective KIT V559D inhibitor CHMFL-KIT-031, which displayed about 10-20 fold selectivity over KIT wt in the biochemical assay (IC50: 28 nM over 168 nM; Kd: 266 nM versus 6640 nM) and in cell (EC50: 176 nM versus 2000 nM for pY703) examination. It also displayed 15∼400-fold selectivity over other primary mutants such as L576P and secondary mutants including T670I, V654A (ATP binding pocket) as well as N822K and D816V (activation loop). In addition, it exhibited a selectivity S score (1) of 0.01 among 468 kinases/mutants in the KINOMEScan™ assay. CHMFL-KIT-031 showed potent inhibitory efficacy for KIT V559D mediated signaling pathways in cell and anti-tumor activity in vivo (Tumor Growth Inhibition: 68.5%). Its superior selectivity would make it a good pharmacological tool for further dissection of KIT V559D mediated pathology in the GISTs.

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