Growth arrest-specific gene 2 suppresses hepatocarcinogenesis by intervention of cell cycle and p53-dependent apoptosis

Abstract

Zollinger-Ellison syndrome (ZES) is characterized by gastric acid hypersecretion causing severe recurrent acid-related peptic disease. Excessive secretion of gastrin can now be effectively controlled with powerful proton pump inhibitors, but surgical management to control gastrinoma itself remains controversial. Based on a thorough literature review, we design a surgical algorithm for ZES and list some significant consensus findings and recommendations: (1) For sporadic ZES, surgery should be routinely undertaken as early as possible not only for patients with a precisely localized diagnosis but also for those with negative imaging findings. The surgical approach for sporadic ZES depends on the lesion location (including the duodenum, pancreas, lymph nodes, hepatobiliary tract, stomach, and some extremely rare sites such as the ovaries, heart, omentum, and jejunum). Intraoperative liver exploration and lymphadenectomy should be routinely performed; (2) For multiple endocrine neoplasia type 1-related ZES (MEN1/ZES), surgery should not be performed routinely except for lesions > 2 cm. An attempt to perform radical resection (pancreaticoduodenectomy followed by lymphadenectomy) can be made. The ameliorating effect of parathyroid surgery should be considered, and parathyroidectomy should be performed first before any abdominal surgery for ZES; and (3) For hepatic metastatic disease, hepatic resection should be routinely performed. Currently, liver transplantation is still considered an investigational therapeutic approach for ZES. Well-designed prospective studies are desperately needed to further verify and modify the current considerations.

Growth arrest–specific 2 protein family: Structure and function

“…GAS2 overexpression inhibits cell division in Xenopus embryos and results in the presence of multinucleated cells 17 . Similarly, upregulated GAS2 in a hepatocellular carcinoma (HCC) cell line (SK‐Hep1) suppresses the G1‐to‐S transition of the cell cycle 13,35 . In contrast, GAS2 in two T‐cell acute lymphoblastic leukaemia cell lines (Jurkat and CCRF‐CEM) facilitates the G1‐to‐S transition of the cell cycle 36 …”

“…Similarly, GAS2 overexpression can increase the etoposide‐induced apoptosis in the MCF7 cells with wild‐type p53, but not in PC3, a type of prostate cancer cell line lacking p53 44 . GAS2 was reported to retard the cellular growth of HCC by enhancing p53‐dependent apoptosis 13,35 . In chicks, probiotics‐induced high expression of GAS2 may be linked to the increased apoptosis of caecal cells upon Salmonella infection 45 .…”

“…The potential roles of GAS2 protein in tumorigenesis of liver cancer, 13,35 leukaemia, 36,48,51‐54 recurrent colorectal cancer, 55‐57 prostate cancer, 58 breast cancer 44,59 or lung adenocarcinoma 60 have been explored, but there are very few studies related to GAS2L1, GAS2L2 and GAS2L3. GAS2L1 was markedly diminished in acute myeloid leukaemia, 61 and the mutation of GAS2L1 may be associated with the neoplastic transformation of meningioma 62 .…”

“…GAS2 mRNA can be detected in the majority of tissues, with the highest levels of GAS2 protein in the liver, lung and kidney tissues 49 . Nevertheless, a lower expression level of GAS2 had been detected in clinical HCC tissues than in the corresponding normal tissues 13,35 . GAS2 can inhibit the carcinogenesis of HCC by influencing the cell cycle and p53‐dependent apoptosis 35 .…”

“…Nevertheless, a lower expression level of GAS2 had been detected in clinical HCC tissues than in the corresponding normal tissues 13,35 . GAS2 can inhibit the carcinogenesis of HCC by influencing the cell cycle and p53‐dependent apoptosis 35 . Additionally, HBxΔ35 can downregulate the expression of GAS2 by binding to the promoter region of GAS2 , thereby resulting in a reduced cell apoptosis level and facilitating the pathogenesis of liver cancer 13 …”