Knockdown of CALM2 increases the sensitivity to afatinib in HER2-amplified gastric cancer cells by regulating the Akt/FoxO3a/Puma axis.

Gastric cancer (GC) is a global health issue that lacks effective treatment options. Afatinib is a tyrosine kinase inhibitor (TKI) that has shown promising results in the treatment of GC. However, resistance to afatinib is inevitable and hampers its clinical application. To date, there is limited knowledge regarding the mechanisms underlying the resistance of GC cells to afatinib. This study aimed to identify novel factors that may contribute to the resistance of GC cells to afatinib. We found that upregulation of calmodulin 2 (CALM2), a member of the CALM family, confers resistance to afatinib in GC cells. Knockdown of CALM2 can overcome the resistance to afatinib by promoting mitochondrial apoptosis in a caspase-dependent manner. Mechanistically, it was found that the downregulation of CALM2 led to the upregulation of the FoxO3a/Puma axis. Inhibition of either FoxO3a or Puma abrogated the effects of CALM2 downregulation in GC cells. In addition, we revealed that CALM2 knockdown inhibited Akt signaling, which is responsible for blocking the FoxO3a/Puma axis. Altogether, our results indicated that CALM2 could be considered a potential target to overcome the resistance of GC cells to afatinib.

Association of Serum Apolipoprotein A5 Concentration with Nonalcoholic Fatty Liver Disease in Ningbo, China.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease characterized by the excessive accumulation of hepatocyte fat and steatosis in the absence of alcohol or any other clear contributing factors to liver injury. NAFLD has been confirmed to be closely associated with obesity, insulin resistance, and dyslipidemia. Genetic polymorphism studies have shown the relations between the apolipoprotein A5 gene (APOA5) and NAFLD. However, the association between the serum ApoA5 level and NAFLD remains unclear. Between September 2018 and August 2019, adults who attended the hospital-based health checkup center were enrolled in this study. Anthropometric examination, laboratory investigations on fasting blood, and abdominal ultrasonography were performed. The serum ApoA5 level was determined by enzyme-linked immunosorbent assay. A total of 517 eligible participants (317 females and 200 males) were involved in this study, with a mean age of 54.7 ± 16.7 years. The mean ApoA5 concentration was 28.8 ± 4.7 µg/ml, among which the males had higher concentration levels than females (29.3 ± 4.5 vs. 28.5 ± 4.7 µg/mL, P=0.04). Serum ApoA5 level was not significantly correlated with NAFLD or metabolic profiles. However, the prevalence rate of hypertriglyceridemia (triglyceride ≥ 1.7 mmol/L) showed a significant inverted "U"-shaped trend in individuals with the serum ApoA5 level of quartile one to quartile four after adjusting the confounding factors. Moreover, individuals with higher serum ApoA5 levels were also more likely to suffer from hyperglycemia. The ApoA5 levels and the prevalence of hypertriglyceridemia are in an inverted "U-shaped" correlation, but there is no significant difference between ApoA5 levels, NAFLD, and metabolic syndrome.