Long Noncoding RNA SNHG12 Promotes Gastric Cancer Proliferation by Binding to HuR and Stabilizing YWHAZ Expression Through the AKT/GSK-3ß Pathway.

BACKGROUND: Gastric cancer (GC) is a malignancy with high morbidity and mortality rates worldwide. SNHG12 is a long noncoding RNA (lncRNA) commonly involved many types of cancers in the contexts of tumorigenesis, migration and drug resistance. Nevertheless, its role in GC proliferation is poorly understood. METHODS: Bioinformatics and qRT-PCR assays were used to analyze the expression of SNHG12 in GC tissues and cells. In vitro and in vivo experiments were conducted to detect the role of SNHG12 in GC development. qRT-PCR, PCR, western blotting (WB), RNA binding protein immunoprecipitation (RIP), immunoprecipitation (IP), immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and in situ hybridization (ISH) were performed to investigate the underlying mechanisms by which SNHG12 promotes GC proliferation. RESULTS: SNHG12 was highly expressed in GC cells and tissues, and predicted poor survival. In vitro and in vivo assays showed that SNHG12 knockdown inhibited GC proliferation, while SNHG12 overexpression promoted GC proliferation. Further experiments confirmed that SNHG12 was mainly located in the cytoplasm and bound to HuR. Bioinformatics analysis predicted that YWHAZ was the common target of SNHG12 and HuR, and that the "SNHG12-HuR" complex enhanced the stability of YWHAZ mRNA. Furthermore, YWHAZ, which was highly expressed in GC, predicted poor survival and promoted GC proliferation by phosphorylating AKT. Rescue assays verified that SNHG12 promoted GC proliferation by activating the AKT/GSK-3ß pathway. CONCLUSIONS: SNHG12 binds to HuR and stabilizes YWHAZ. SNHG12 promotes GC proliferation via modulation of the YWHAZ/AKT/GSK-3ß axis in vitro and in vivo. Thus, SNHG12 could become a novel therapeutic target for anti-tumor therapy.

YY1-modulated long non-coding RNA SNHG12 promotes gastric cancer metastasis by activating the miR-218-5p/YWHAZ axis.

Long non-coding RNA (lncRNA) small nucleolar RNA host gene 12 (SNHG12) plays important roles in the pathogenesis and progression of cancers. However, the role of SNHG12 in the metastasis of gastric cancer (GC) has not yet been thoroughly investigated. In the present study, we demonstrated that SNHG12 was upregulated in GC tissues and cell lines. In addition, the expression level of SNHG12 in GC samples was significantly related to tumor invasion depth, TNM stage and lymph node metastasis and was associated with disease-free survival (DFS) and overall survival (OS) in GC patients. In vivo and in vitro assays indicated that SNHG12 promotes GC metastasis and epithelial-mesenchymal transition (EMT). Bioinformatics and mechanistic analyses revealed that SNHG12 can directly target miR-218-5p to regulate YWHAZ mRNA, forming an SNHG12/miR-218-5p/YWHAZ axis and decreasing the ubiquitination of ß-catenin. In addition, SNHG12 stabilizes CTNNB1 mRNA by binding with HuR, thus activating the ß-catenin signaling pathway. Further analysis also revealed that the transcription factor YY1 negatively modulates SNHG12 transcription. In conclusion, SNHG12 is a potential prognostic marker and therapeutic target for GC. Negatively modulated by YY1, SNHG12 promotes GC metastasis and EMT by regulating the miR-218-5p/YWHAZ axis and stabilizing CTNNB1 via activation of the ß-catenin signaling pathway.

Preoperative imaging evaluation of the absolute indication criteria for endoscopic submucosal dissection in early gastric cancer patients.

INTRODUCTION: Gastric cancer (GC) is a common malignant tumor with a high mortality rate. AIM: To determine the accuracy of preoperative imaging information obtained from the combined use of general gastroscopy (GS), endoscopic ultrasonography (EUS), and multi-detector computed tomography (MDCT) regarding absolute indication of endoscopic submucosal dissection (ESD) in early gastric cancer (EGC). MATERIAL AND METHODS: The relationship between clinical features of 794 EGC patients and lymph node metastasis (LNM) was analyzed. Multivariate logistic regression analysis was used to investigate the risk factors for LNM. Additionally, the accuracy of diagnosis of imaging techniques for ESD indications was determined by receiver operating characteristic (ROC) analysis. RESULTS: Data showed that tumor size > 2 cm (p = 0.0071), T1b stage (p < 0.0001), undifferentiated histology (p < 0.0001), and vascular invasion (p = 0.0007) were independent risk factors for LNM in patients with EGC. Indications for ESD have a specificity of 100% for the diagnosis of patients with LNM. Additionally, the diagnostic efficacy of the use of GS, EUS, and MDCT in identifying node positive status, T1a disease, tumor size ≤ 2 cm, and ulceration was found to be moderate with area under the curve (AUC) of receiver operating characteristic curve (ROC) of 0.71, 0.64, 0.72, and 0.68, respectively. Furthermore, the use of imaging techniques for overall indication criteria for ESD had a moderate utility value with an AUC of 0.71. CONCLUSIONS: Our data suggested that, based on the combined use of GS, EUS, and MDCT, a high specificity of patient selection for ESD treatment can be achieved.

Study protocol of a multicenter phase III randomized controlled trial investigating the efficiency of the combination of neoadjuvant chemotherapy (NAC) and neoadjuvant laparoscopic intraperitoneal hyperthermic chemotherapy (NLHIPEC) followed by R0 gastrectomy with intraoperative HIPEC for advanced gastric cancer (AGC): dragon II trial.

BACKGROUND: Even though treatment modalities such as adjuvant systemic radio-chemotherapy and neoadjuvant chemotherapy (NAC) have individually have improved overall survival (OS) and progression-free survival (PFS) rates in advanced Gastric Cancer (AGC), the peritoneum still presides as a common site of treatment failure and disease recurrence. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) has been acknowledged as prophylaxis for peritoneal carcinomatosis (PC) in AGC patients and in this study, we aim at investigating the safety and efficacy of the combination of neoadjuvant laparoscopic HIPEC (NLHIPEC) with NAC in the neoadjuvant phase followed by surgery of curative intent with intraoperative HIPEC followed by adjuvant chemotherapy (AC). METHODS: In this multicenter Phase III randomized controlled trial, 326 patients will be randomly separated into 2 groups into a 1:1 ratio after laparoscopic exploration. The experiment arm will receive the proposed comprehensive Dragon II regimen while the control group will undergo standard R0 D2 followed by 8 cycles of AC with oxaliplatin with S-1 (SOX) regimen. The Dragon II regimen comprises of 1 cycle of NLHIPEC for 60mins at 43 ± 0.5 °C with 80 mg/m2 of Paclitaxel followed by 3 cycles of NAC with SOX regimen and after assessment, standard R0 D2 gastrectomy with intraoperative HIPEC followed by 5 cycles of SOX regimen chemotherapy. The end-points for the study are 5 year PFS, 5 year OS, peritoneal metastasis rate (PMR) and morbidity rate. DISCUSSION: This study is one of the first to combine NLHIPEC with NAC in the preoperative phase which is speculated to provide local management of occult peritoneal carcinomatosis or peritoneal free cancer cells while NAC will promote tumor downsizing and down-staging. The addition of the intraoperative HIPEC is speculated to manage dissemination due to surgical trauma. Where the roles of intraoperative HIPEC and NAC have individually been investigated, this study provides innovative insight on a more comprehensive approach to management of AGC at high risk of peritoneal recurrence. It is expected that the combination of NLHIPEC with NAC and HIPEC will increase PFS by 15% and decrease PMR after gastrectomy of curative intent. TRIAL REGISTRATION: World Health Organization Clinical Trials - International Registry Platform (WHO-ICTRP) with Registration ID ChiCTR1900024552, Registered Prospectively on the 16th July, 2019.

Effect of apatinib plus neoadjuvant chemotherapy followed by resection on pathologic response in patients with locally advanced gastric adenocarcinoma: A single-arm, open-label, phase II trial.

BACKGROUND: The evidence of combining neoadjuvant chemotherapy with targeted therapy for patients with locally advanced gastric cancer is inadequate. We conducted a single-arm phase II trial to evaluate the efficacy and safety of S-1, oxaliplatin and apatinib (SOXA) in patients with locally advanced gastric adenocarcinoma. METHODS: Treatment-naïve patients received three preoperative cycles of S-1 (80-120 mg/day on days 1-14) and oxaliplatin (130 mg/m2 on day 1) and two cycles of apatinib (500 mg/day for 21 days) at 3-week intervals, followed by surgery. The primary end-point was pathologic response rate (pRR). This trial is registered at ChiCTR.gov.cn: ChiCTR-OPC-16010061. RESULTS: Of 29 patients included, median age was 60 (range, 43-73) years; 20 (69.0%) were male. The pRR was 89.7% (95% confidence interval [CI], 72.7%-97.8%; 26 of 29 patients; P < 0.001) with 28 patients treated with surgery. All 29 patients were available for preoperative response evaluation, achieving an objective response rate of 79.3% (95% CI, 60.3%-92.0%) and a disease control rate of 96.6% (95% CI, 82.2%-99.9%). The margin-free resection rate was 96.6% (95% CI, 82.2%-99.9%). The pathologic complete response rate was 13.8% (95%CI, 1.2%-26.3%). Downstaging of overall TNM stage was observed in 16 (55.2%) patients. During neoadjuvant therapy, 10 (34.5%) patients had grade ≥III adverse events. No treatment-related death occurred. Surgery-related complications were observed in 12 of 28 (42.9%) patients. CONCLUSION: SOXA followed by surgery in patients with locally advanced gastric adenocarcinoma showed favourable activity and manageable safety. A randomised controlled trial in locally advanced gastric or oesophagogastric junction adenocarcinoma is ongoing (ClinicalTrials.gov: NCT04208347).

Optimization of perioperative approaches for advanced and late stages of gastric cancer: clinical proposal based on literature evidence, personal experience, and ongoing trials and research.

BACKGROUND: The high incidence of gastric cancer (GC) and paradoxical high prevalence of advanced stage GC, amounting to around 2/3 at time of diagnosis, have urged doctors and researchers around the world not only to ameliorate the detection rate of GC at early stages but also to optimize the clinical management of GC at advanced stages. CONTENT: We hereby recommend a more goal-oriented multimodality approach with objectives to increase survival rate and improve survival status. Based on precision and accurate clinical staging at diagnosis, we suggest that advanced stage GC (AGC) patients should be channeled into different treatment plans according to their disease status where they can be subjected to comprehensive measures involving chemo, radio, immunological, or target therapies depending on the pathophysiological behavior of their tumor. Patients assessed as potentially resectable cT4N + M0 can undergo neoadjuvant chemotherapy with intent of tumor downsizing and downgrading followed by surgery with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) to decrease the incidence of peritoneal dissemination due to surgical trauma and adjuvant chemotherapy and radiation in cases of bulky nodal metastasis. In cases with distal metastasis, conversion therapy is recommended with the possibility of surgery of curative intent in case of favorable response. The options of alternate treatment options such as trans-catheter arterial chemoembolization (TACE) for limited liver lesions or neoadjuvant intraperitoneal plus systemic chemotherapy (NIPS) for peritoneal carcinomatosis have to be negotiated. With surgery as the cornerstone for cancer treatment, there is acknowledgment of the significance of perioperative comprehensive approaches but there has not been some consensus guiding clinical application. Henceforth, in this review, based on past literature, current guidelines and ongoing clinical trials, we have shared a proposal of the current treatment modalities in practice for the advanced stages of gastric cancer. CONCLUSION: Even though surgery is the golden standard of radical cancer treatment, clinical reality shows that without proper perioperative management, patients undergoing radical resections manifest high rates of recurrence and metastasis. Hence, in this review, we have outlined a clinical agenda to optimize the management of advanced stage GC with objective to improve survival outcome and quality of life of patients.

Expanding the indication of endoscopic submucosal dissection for undifferentiated early gastric cancer is safe or not?

BACKGROUND: Endoscopic submucosal dissection (ESD) has gained more popularity in the treatment of early gastric cancer (EGC). Although there is a lack of confirmed evidence for the feasibility of ESD for undifferentiated EGC. The aim of the study was to investigate the feasibility of ESD with expanded indications for undifferentiated EGC patients. METHODS: Data from patients with undifferentiated EGC (including signet-ring cell carcinoma, mucinous adenocarcinoma, mixed adenocarcinoma, and poorly differentiated adenocarcinoma) who underwent radical surgical resection were retrospectively reviewed. The relationship between the clinical parameters and the incidence of lymph node metastasis (LNM) was investigated. RESULTS: A total of 517 patients were included in this study. The results showed that LNM was significantly associated with ulceration, tumor size, depth of invasion, lymphatic invasion, vascular invasion, and perineural invasion. Multivariate stepwise logistic regression analysis revealed that tumor size (OR = 1.61, 95% CI = 1.03-2.52, P = 0.0367), depth of tumor invasion (OR = 2.77, 95% CI = 1.66-4.63, P = 0.0001), and lymphatic invasion (OR = 14.74, 95% CI = 1.58-137.36, P = 0.0182) were independent risk factors for LNM. In the patients who would be included under the new proposed guidelines for ESD, including men with mucosal tumors ≤2 cm and without ulceration or lymphatic or venous infiltration, LNM was present in 11.9% (14/118). CONCLUSION: Caution to be exercised in expanding application of ESD should be carefully weighed in undifferentiated EGC.

Prophylactic HIPEC with radical D2 gastrectomy improves survival and peritoneal recurrence rates for locally advanced gastric cancer: personal experience from a randomized case control study.

BACKGROUND: To investigate the implications of prophylactic intraoperative Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with D2 radical gastrectomy for locally advanced Gastric Cancer (AGC) in a randomized case control study. METHOD: Eighty consecutive patients with locally AGC were randomly separated into 2 groups: HIPEC group (Curative Resection + intraoperative HIPEC with cisplatin 50 mg/m2 at 42.0 ± 1.0 °C for 60 min) and Control group (Curative Resection only). Intraoperative and post-operative events, clinical recovery, morbidity and the disease-free survival (DFS) rates were closely monitored. RESULTS: Among the 40 HIPEC group patients, the highest intracranial temperature recorded during the procedure was 38.2 °C but the patient made an eventless recovery. Mild renal dysfunction, hyperbilirubinemia and mild liver dysfunction were recorded in the HIPEC group but their incidences were found to be statistically insignificant when compared with the control group (P > 0.05). The initial post-operative analysis revealed shorter post-operative stay for in the HIPEC group but further analysis revealed that it was related to the incidence of postoperative complication. During a median follow-up time of 41 months, there were 9/39 and 15/38 cases of disease progression in HIPEC and Control groups respectively, with a more favorable 3-year DFS (76.9% vs 60.5%) and a lower peritoneal recurrence rate (5% vs 30%) in the HIPEC group. CONCLUSION: Prophylactic HIPEC with radical D2 Gastrectomy is safe and shows favorable survival and peritoneal recurrence rates for AGC with acceptable morbidity. Nevertheless, more structured multi-centered RCT should be carried out for more substantial evidence.

Correction to: Prophylactic HIPEC with radical D2 gastrectomy improves survival and peritoneal recurrence rates for locally advanced gastric cancer: personal experience from a randomized case control study.

Following publication of the original article [1], the authors reported the following errors/updates.

Impact of intra-peritoneal fat distribution on intra-operative bleeding volume with D2 lymphadenectomy in Chinese patients with gastric cancer.

OBJECTIVE: To explore the quantitative measurements and evaluation of intra-peritoneal fat distribution by MDCT and its significance in predicting intra-operative bleeding volume during D2 lymphadenectomy in gastric cancer (GC) patients. METHODS: From June 2016 to September 2017, GC patients scheduled for open gastrectomy with D2 lymph-node dissection were enrolled. According to the BMI, the subjects were then classified as normal BMI(BMI<25 kg/m2); overweight (BMI = 25-30 kg/m2) and obese (BMI≥30 kg/m2). According to the intraoperative blood loss (IBL), the patients were further separated into high IBL (IBL; ≥ 300 ml) or low IBL (<300 ml). Clinicopathological parameters between the groups were statistically compared and univariate and multivariate analysis were used to identify predictive factors such as intra-peritoneal fat areas (IFA) and intra-peritoneal fat areas ratio (IFAR) for high IBL. RESULTS: A total of 226 patients were included in the study where 53 patients underwent distal while 173 underwent total gastrectomy. According to the BMI classification, there were 25 normal BMI, 108 overweight and 25 obese subjects. According to the IBL, there were 98 high IBL and 128 low IBL subjects. IFA and IFAR were significantly greater in the high IBL group than in the low IBL group. There was no significant difference in any other clinicopathological factors between the high IBL group and the low IBL group. Multivariate analysis revealed that high IFA and IFAR independently predicted high IBL. CONCLUSION: The use of MDCT to evaluate the precise distribution of abdominal fat during preoperative examination can prompt surgeons to develop techniques to decrease intraoperative bleeding in obese patients. Nevertheless, it is yet necessary to be surgically more meticulous when dealing with patients with high IFA or high IFA/IFAR in order to improve the outcome of D2 gastrectomy.