The protocol of a prospective, multicenter, randomized, controlled phase III study evaluating different cycles of oxaliplatin combined with S-1 (SOX) as neoadjuvant chemotherapy for patients with locally advanced gastric cancer: RESONANCE-II trial.

BACKGROUND: Curing locally advanced gastric cancer through surgery alone is difficult. Adjuvant and neoadjuvant chemotherapy bring potential benefits to more patients with gastric cancer based on several clinical trials. According to phase II studies and guidelines, SOX regimen as neoadjuvant chemotherapy is efficient. However, the optimal duration of neoadjuvant chemotherapy has not been established. In this study, we will evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer. METHODS: RESONANCE-II trial is a prospective, multicenter, randomized, controlled phase III study which will enroll 524 patients in total. Eligible patients will be registered, pre-enrolled and receive three cycles of SOX, after which tumor response evaluations will be carried out. Those who show stable disease or progressive disease will be excluded. Patients showing complete response or partial response will be enrolled and assigned into either group A for another three cycles of SOX (six cycles in total) followed by D2 surgery; or group B for D2 surgery (three cycles in total). The primary endpoint is the rate of pathological complete response and the secondary endpoints are R0 resection rate, three-year disease-free survival, five-year overall survival, and safety. DISCUSSION: This study is the first phase III randomized trial to compare the cycles of neoadjuvant chemotherapy using SOX for resectable locally advanced cancer. Based on a total of six to eight cycles of perioperative chemotherapy usually applied in locally advanced gastric cancer, patients in group A can be considered to have completed all perioperative chemotherapy, the results of which may suggest the feasibility of using chemotherapy only before surgery in gastric cancer. TRIAL REGISTRATION: Registered prospectively in the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) with registration number ChiCTR1900023293 on May 21st, 2019.

Proviral insertion in murine lymphomas 2 promotes stomach cancer progression by regulating apoptosis via reactive oxygen species-triggered endoplasmic reticulum stress.

Gastric cancer is one of the most fatal cancers worldwide. The incidence and death rates are still increasing for gastric cancer. Increasing studies have shown that proviral insertion in murine lymphomas 2 (PIM2) functions as critical regulator of multiple cancers. However, it remains unknown whether and how PIM2 regulates gastric cancer progression. In this study, PIM2 was increased in the gastric cancer tissues of patients. Patients with high PIM2 expression levels had significantly shorter survival than those with low PIM2 expression. PIM2 knockdown reduced proliferation, migration and invasion in vitro by up-regulating E-cadherin, and down-regulating N-cadherin and Vimentin. Knockdown of PIM2 induced apoptosis in gastric cancer cells, which was regulated by endoplasmic reticulum (ER) stress, as evidenced by the increased expression levels of Activating transcription factor (ATF) 6, ATF4, X-box- binding protein-1 (XBP-1) and C/EBP homologous protein (CHOP). In addition, our data showed that PIM2 silence induced reactive oxygen species (ROS) production, leading to the activation of c-Jun N-terminal kinase (JNK). Importantly, we found that PIM2 knockdown-induced apoptosis and ER stress could be abolished by reducing reactive oxygen species (ROS) generation. In vivo, PIM2 knockdown showed a significant reduction in SGC-7901 xenograft tumor size. In summary, our findings provided experimental evidence that PIM2 might function as an important oncogene in gastric cancer, which supplied promising target for developing new therapeutic strategy in gastric cancer.

Long non-coding RNA ABHD11-AS1 boosts gastric cancer development by regulating miR-361-3p/PDPK1 signalling.

Gastric cancer (GC) is one of the most common cancers in gastrointestinal malignant tumours. Long non-coding RNAs were widely reported to play a significant role in the regulation of occurrence or development of tumours. Bioinformatics analysis and a wide range of experiments were conducted to explore the expression status, specific function and molecular mechanism of long non-coding RNA ABHD11 antisense RNA 1 (ABHD11-AS1). ABHD11-AS1 knockdown repressed cell proliferation but enhanced cell apoptosis in function. We proved that miR-361-3p directly combines with the 3'wUTR of PDPK2 and ABHD11-AS1 cooperated with miR-361-3p to modulate PDPK2 mRNA and protein levels. Rescue assays confirmed that the miR-361-3p silence reversed the suppressive effect of ABHD11-AS1 deficiency. In summary, ABHD11-AS1 boosts GC development by regulating miR-361-3p/PDPK1 signalling.