Hypoxia and dysregulation of microRNAs (miRNAs) have been identified as crucial factors in carcinogenesis. However, the potential mechanisms of HIF-1α and miR-421 in gastric cancer have not been well elucidated. In this study, we found that miR-421 was up-regulated by HIF-1α. Overexpression of miR-421 promoted metastasis, inhibited apoptosis, and induced cisplatin resistance in gastric cancer in vivo and in vitro. E-cadherin and caspase-3 were identified as targets of miR-421. Besides, relative mRNA expression of miR-421 was significantly increased in gastric cancer tumor tissues compared with non-tumor tissues in a cohort of gastric cancer specimens (n=107). The expression of miR-421 was higher in advanced gastric cancers compared with localized ones. Moreover, Kaplan–Meier analysis illustrated that those patients with low levels of miR-421 had a significant longer overall survival (p = 0.006) and time to relapse (p = 0.007). Therefore, miR-421 could serve as an important prognostic marker and a potential molecular target for therapy in gastric cancer.

Purpose: Targeting human epidermal growth factor receptor 2 (HER2) therapy is currently considered as the standard treatment for HER2-positive (HER2 IntroductionPrevious studies have demonstrated that the human epidermal growth factor receptor 2 (HER2) signaling pathway is a critical driver of carcinogenesis and tumor progression in approximately 7% to 34% of total patients with gastric cancer (1-3). Targeting HER2 combined with chemotherapy has been the first-line treatment for HER2-positive (HER2 þ ) advanced gastric cancer (1, 4). However, only few patients with HER2 þ gastric cancer responded to the HER2-targeting agents. Recently, preliminary results of a phase III trials evaluating the efficacy of lapatinib, a dual tyrosine kinase inhibitor (TKI) targeting both HER2 and epithelial growth factor receptor (EGFR), in conjunction with cytotoxic chemotherapy for HER2 þ advanced or metastatic gastric cancer (LOGiC study) were released. Unfortunately, the addition of lapatinib to chemotherapy did not significantly improve OS, the primary endpoint, compared with chemotherapy alone. The median OS was 12.2 versus 10.5 months, respectively (HR, 0.91; 95% CI, 0.73-1.12; P ¼ 0.3492). The median PFS was 6.0 versus 5.4 months, response rate 53% versus 40% and duration of response 7.3 versus 5.6 months (5). Based on the data from LOGiC study, the observed unsatisfactory survival prolongation could be explained by the limited initial response to lapatinib for patients with HER2

Apatinib is a new treatment option for advanced gastric cancer. Apatinib is expected to have a broader application when it has been evaluated worldwide. The key issues are to find biomarkers and overcome drug resistance.

Checkpoint blockade therapy has emerged as a novel approach for cancer immunotherapy in several malignancies. However, patient prognosis and disease progression relevant to immune checkpoints in gastric tumor microenvironment are not defined. This study aims to investigate the expression and prognostic significance of immune checkpoints within gastric cancer. In the study, a cohort of 398 cancer tissues from stage I to IV gastric cancer patients were assessed for programmed cell death 1 ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) infiltration using immunohistochemistry to ascertain their survival correlation. The data revealed that higher TIL density correlated with less risk of disease progression, and exhibited survival benefits in gastric cancer patients, and PD-L1 positivity showed a significant association with the presence of high TIL infiltration. Furthermore, real-time quantitative polymerase chain reaction was performed to detect expression of multiple immune checkpoints with the relation to clinical outcome in 139 samples randomly selected from the same cohort, and higher messenger RNA levels of most immune checkpoints were associated with favorable outcome, while consistently showing a positive correlation with interferon gamma levels. In situ hybridization was used to determine the localization of Epstein-Barr virus (EBV) in 97 specimens, and showed EBV-positive gastric cancer samples correlated with PD-L1 expression and increased TIL density. These results suggest that induction of immune checkpoint within gastric cancer patients reflects a high immune infiltration density, especially in those with EBV-associated gastric cancer, which may direct patient selection for checkpoint blockade therapy.