Liao Xia, Zhang Yaoyao, Xu Binghui, Ali Arshad, Liu Xin, Jia Qingan
Department of Nutrition, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China.
J Cancer. 2021 Aug 24;12(20):6071-6080. doi: 10.7150/jca.62141. eCollection 2021.
Hepatocellular carcinoma (HCC) is a drastic problem in China. Oxaliplatin, a platinum-based chemotherapy drug, has limited efficacy in treating HCC, characterized by intrinsic and acquired resistance. Inositol hexaphosphate (IP6), a carbohydrate abundant in grains, has contributed to the rising popularity of whole grain products consumption for the potential protection against dozens of diseases. However, the therapeutic potential of IP6 in halting the progression of HCC remains unclear, especially in combination with oxaliplatin. The anti-proliferation and anti-migration effects of IP6 were evaluated and . The synergistic and sequential anti-proliferative effect with IP6 and oxaliplatin were also evaluated in HCC. Finally, the role of CCN2-LRP6-β-catenin-ABCG1 signaling in oxaliplatin resistance and IP6 treatment was evaluated. We proved that IP6 treatment exhibited independent anticancer effect and synergistic anti-proliferative effects in combination with oxaliplatin in HCC. Specifically, up-regulation of ABCG1 and CCN2 were associated with oxaliplatin resistance. ABCG1 was acting as a downstream molecule of the CCN2-LRP6-Wnt/β-catenin signaling pathway in HCC cells. The IP6 treatment exhibited inhibition of CCN2-LRP6-Wnt/β-catenin signaling pathway and downregulation of ABCG1 in HCC cells. When combined with ABCG1 knocking down in HCC cells, the anti-proliferative effect of oxaliplatin was partly impaired in combination with IP6. We suggested that IP6 treatment renders HCC sensitive to oxaliplatin and breaking the CCN2-LRP6-β-catenin-ABCG1 signaling pathway is one of the mechanism after IP6 treatment.
肝细胞癌（HCC）在中国是一个严峻的问题。奥沙利铂是一种铂类化疗药物，在治疗HCC方面疗效有限，存在内在和获得性耐药。肌醇六磷酸（IP6）是谷物中丰富的一种碳水化合物，由于其对多种疾病具有潜在的保护作用，使得全谷物产品的消费日益普遍。然而，IP6在阻止HCC进展方面的治疗潜力仍不清楚，尤其是与奥沙利铂联合使用时。评估了IP6的抗增殖和抗迁移作用。还评估了IP6与奥沙利铂在HCC中的协同和序贯抗增殖作用。最后，评估了CCN2-LRP6-β-连环蛋白-ABCG1信号通路在奥沙利铂耐药和IP6治疗中的作用。我们证明，IP6治疗在HCC中表现出独立的抗癌作用，并与奥沙利铂联合具有协同抗增殖作用。具体而言，ABCG1和CCN2的上调与奥沙利铂耐药相关。在HCC细胞中，ABCG1作为CCN2-LRP6-Wnt/β-连环蛋白信号通路的下游分子。IP6治疗在HCC细胞中表现出对CCN2-LRP6-Wnt/β-连环蛋白信号通路的抑制和ABCG1的下调。当与HCC细胞中ABCG1敲低联合时，奥沙利铂与IP6联合的抗增殖作用部分受损。我们认为，IP6治疗使HCC对奥沙利铂敏感，而破坏CCN2-LRP6-β-连环蛋白-ABCG1信号通路是IP6治疗后的机制之一。
