Value of glycogen synthase 2 in intrahepatic cholangiocarcinoma prognosis assessment and its influence on the activity of cancer cells

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor with increasing incidence worldwide. Metabolic reprogramming caused by metabolic related gene disorders is a prominent hallmark of tumors, among which Glycogen Synthase 2 (GYS2) is the key gene responsible for regulating cellular energy metabolism, and its expression disorders are closely related to various tumors and glycometabolic diseases. However, we still know nothing about its role in ICC. This study is intended to reveal the functional role of GYS2 in the ICC progress and explore the underlying mechanism. Based on the integrated pan-cancer analysis of GYS2 in the GEPIA database, the expression of GYS2 in paired ICC and adjacent non tumor tissues was detected by qPCR. It was found that the expression of GYS2 was significantly down-regulated in ICC. Further analysis showed that its low expression was not only associated with the degree of pathological differentiation, tumor size, microvascular invasion and lymph node metastasis, but also an independent risk factor for unfavorable prognosis. Functional studies have shown that GYS2 overexpression can significantly impair the proliferation, replication, cloning, migration and invasion of cholangiocarcinoma cells, while the silencing GYS2 dramatically promotes the development of the aforementioned phenotypes, the underlying mechanism may be that GYS2 activates the P53 pathway. In conclusions,low GYS2 expression in ICC predicted unfavorable patient outcomes; GYS2 overexpression could significantly impair the proliferation, migration and invasion of cholangiocarcinoma cells via activating the P53 pathway and GYS2 was expected to become a potential therapeutic target for such patients.

肝内胆管癌（Intrahepatic cholangiocarcinoma, ICC）是全球发病率逐年升高的第二大常见原发性肝脏肿瘤。由代谢相关基因紊乱介导的代谢重编程是肿瘤的显著特征之一，其中糖原合酶2（Glycogen Synthase 2, GYS2）是调控细胞能量代谢的关键基因，其表达异常与多种肿瘤及糖代谢疾病密切相关。然而目前学界对其在ICC中的作用尚一无所知。本研究旨在揭示GYS2在ICC进展中的功能角色，并探究其潜在作用机制。本研究基于GEPIA数据库开展GYS2的泛癌整合分析，并通过qPCR检测配对ICC组织与癌旁非肿瘤组织中GYS2的表达水平，结果发现GYS2在ICC中显著下调。进一步分析显示，其低表达不仅与病理分化程度、肿瘤大小、微血管侵犯及淋巴结转移相关，还是患者不良预后的独立危险因素。功能实验表明，过表达GYS2可显著抑制胆管癌细胞的增殖、复制、克隆形成、迁移及侵袭能力；而沉默GYS2则会显著促进上述表型的发生发展，其潜在机制可能为GYS2激活P53通路。综上，ICC中GYS2低表达预示患者不良预后；过表达GYS2可通过激活P53通路显著抑制胆管癌细胞的增殖、迁移及侵袭能力，GYS2有望成为此类患者的潜在治疗靶点。