Implication of Leptin-Signaling Proteins and Epstein-Barr Virus in Gastric Carcinomas

Abstract

We investigated the clinicopathological implications of leptin-signaling proteins and Epstein-Barr virus (EBV)-infection status in gastric carcinomas. Immunohistochemistry for leptin signalling-related proteins (leptin, leptin-receptor, pSTAT3, ERK, pAkt, mTOR and HIF-1 alpha), and in situ hybridization for EBV-encoded small RNAs was performed in 343 cases of gastric carcinomas. The siRNA against leptin-receptor was transfected into three stomach cancer cell lines, and western blot for caspase 3 was performed. The TNM stage was a prognostic factor in all 343 patients, and was negatively correlated with expression of leptin, pSTAT3, ERK, pAkt, mTOR and HIF-1 alpha (P < 0.05). Leptin-receptor expression was correlated with poor survival in 207 patients of the advanced gastric cancer (AGC) subgroup, 139 of the Lauren diffuse group, and in 160 patients with lymph node metastasis (P < 0.05, respectively). Additionally, in stomach cancer cells, cleaved caspase 3 level increased by leptin-receptor inhibition, that is, apoptosis increased. Interestingly, EBV-positive AGC (n = 29) tended to show better survival of patients than EBV-negative AGC (n = 178) (P = 0.06). pAkt expression was related with a good survival of 32 patients (9%) in the EBV-positive subgroup, but was not an independent prognostic factor. Among, leptin signaling-related proteins, expressions of leptin-receptor and mTOR were different between EBV-positive subgroup and EBV-negative subgroup (P < 0.05, respectively). In conclusion, leptin-signaling proteins and EBV status show different significance on patient survival, according to subsets of gastric carcinomas. The leptin-receptor may predict poor patient prognosis in the AGC, Lauren diffuse and lymph node metastasis subgroups, while EBV-positive status can show a good prognosis in the AGC. Each leptin signaling-related protein may be differently involved in carcinogenesis of EBV-negative and EBV-positive subsets.

Prognostic Value and Clinicopathological Significance of p-stat3 Among Gastric Carcinoma Patients

“…These studies were published between 2004 and 2015. In all included studies, 1 study 27 was conducted in America populations, and others were conducted in Asian populations, including 3 studies from Japan, 24 , 26 , 38 4 from Korean, 28 – 29 , 35 , 41 and 15 from China. 18 , 25 , 30 – 34 , 36 – 37 , 39 – 40 , 42 – 45 The total number of patients was 2872, with a median number of 98 patients each study (range: 50–343).…”

“…In 11 included studies, 25 , 27 , 33 , 36 – 37 , 39 – 40 , 42 – 45 p-stat3 expression was quantified according to the percentage of positive cells and staining intensity. In other 12 included studies, 18 , 24 , 26 , 28 – 32 , 34 – 35 , 38 , 41 p-stat3 expression was quantified according to the percentage of positive cells alone. In most studies, the positive staining of p-stat3 was located in nucleus, others located in nucleus and cytoplasm 26 , 36 , 40 , 30 , 33 , 44 All included studies reported the association between p-stat3 expression and clinicopathological characteristics, and 11 studies reported data on the effect of p-stat3 expression on overall survival.…”

“…To evaluate the quality of included studies in the meta-analysis, we performed a qualitative assessment for each study according to the ELCWP quality scale. In all studies, 9 studies 36 – 41 , 43 – 45 could not be scored in the category of “results analysis,” because they did not provide survival data. The global quality score ranged 34.82% to 84.44%, with a median of 55.92% (Table 2 ).…”

The potential role of leptin in tumor invasion and metastasis

“…With respect to gastric carcinoma Ob-R expression was correlated with poor survival in 47% of patients with lymph node metastasis, 60% of the patients with advanced gastric cancer, and 41% of the cases defined as Lauren diffuse pathology [103] (Table 1). Of note, gastric cancer has been classified in many different ways such as Lauren, World Health Organization (WHO), and Borrmann classifications [104].…”

Diabetes-associated dysregulated cytokines and cancer

“…For instance, preclinical evidence has revealed that leptin stimulates esophageal, colorectal, prostate and breast cancer cell proliferation [62-66] and is responsible for the association between diabetes and prostate cancer [67]. The leptin-receptor might predict poor prognosis in patient with advanced gastric cancer (AGC) [68]. In addition, a pooled analysis from three cohorts by Stolzenberg-Solomon et al supports an relationship between enhancing leptin levels and pancreatic cancer [69].…”