State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, Collaborative Innovation Center for Diagnosis & Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.
Microbiome Research Centre, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia.
J Exp Clin Cancer Res. 2021 Jan 4;40(1):1. doi: 10.1186/s13046-020-01803-8.
Hepatitis B virus (HBV) infection is a crucial risk factor for hepatocellular carcinoma (HCC). However, its underlying mechanism remains understudied.
Microarray analysis was conducted to compare the genes and miRNAs in liver tissue from HBV-positive and HBV-negative HCC patients. Biological functions of these biomarkers in HBV-related HCC were validated via in vitro and in vivo experiments. Furthermore, we investigated the effect of HBV on the proliferation and migration of tumor cells in HBV-positive HCC tissue. Bioinformatics analysis was then performed to validate the clinical value of the biomarkers in a large HCC cohort.
We found that a gene, MINPP1 from the glycolytic bypass metabolic pathway, has an important biological function in the development of HBV-positive HCC. MINPP1 is down-regulated in HBV-positive HCC and could inhibit the proliferation and migration of the tumor cells. Meanwhile, miRNA-30b-5p was found to be a stimulator for the proliferation of tumor cell through glycolytic bypass in HBV-positive HCC. More importantly, miRNA-30b-5p could significantly downregulate MINPP1 expression. Metabolic experiments showed that the miRNA-30b-5p/MINPP1 axis is able to accelerate the conversion of glucose to lactate and 2,3-bisphosphoglycerate (2,3-BPG). In the HBV-negative HCC cells, miRNA-30b-5p/MINPP1 could not regulate the glycolytic bypass to promote the tumorigenesis. However, once HBV was introduced into these cells, miRNA-30b-5p/MINPP1 significantly enhanced the proliferation, migration of tumor cells, and promoted the glycolytic bypass. We further revealed that HBV infection promoted the expression of miRNA-30b-5p through the interaction of HBV protein P (HBp) with FOXO3. Bioinformatics analysis on a large cohort dataset showed that high expression of MINPP1 was associated with favorable survival of HBV-positive HCC patients, which could lead to a slower progress of this disease.
Our study found that the HBp/FOXO3/miRNA-30b-5p/MINPP1 axis contributes to the development of HBV-positive HCC cells through the glycolytic bypass. We also presented miRNA-30b-5p/MINPP1 as a novel biomarker for HBV-positive HCC early diagnosis and a potential pharmaceutical target for antitumor therapy.
乙型肝炎病毒（HBV）感染是肝细胞癌（HCC）的一个重要危险因素。然而，其潜在机制仍未得到充分研究。
采用微阵列分析比较 HBV 阳性和 HBV 阴性 HCC 患者肝组织中的基因和 miRNA。通过体外和体内实验验证这些生物标志物在 HBV 相关 HCC 中的生物学功能。此外，我们研究了 HBV 对 HBV 阳性 HCC 组织中肿瘤细胞增殖和迁移的影响。然后，进行生物信息学分析以验证生物标志物在大型 HCC 队列中的临床价值。
我们发现糖酵解旁路代谢途径中的基因 MINPP1 在 HBV 阳性 HCC 的发生发展中具有重要的生物学功能。MINPP1 在 HBV 阳性 HCC 中下调，可抑制肿瘤细胞的增殖和迁移。同时，miRNA-30b-5p 通过 HBV 阳性 HCC 中的糖酵解旁路被发现可刺激肿瘤细胞的增殖。更重要的是，miRNA-30b-5p 可显著下调 MINPP1 的表达。代谢实验表明，miRNA-30b-5p/MINPP1 轴能够加速葡萄糖转化为乳酸和 2,3-二磷酸甘油（2,3-BPG）。在 HBV 阴性 HCC 细胞中，miRNA-30b-5p/MINPP1 不能调节糖酵解旁路以促进肿瘤发生。然而，一旦将 HBV 引入这些细胞，miRNA-30b-5p/MINPP1 则显著增强肿瘤细胞的增殖、迁移，并促进糖酵解旁路。我们进一步揭示了 HBV 感染通过 HBV 蛋白 P（HBp）与 FOXO3 的相互作用促进 miRNA-30b-5p 的表达。对大型队列数据集的生物信息学分析表明，MINPP1 的高表达与 HBV 阳性 HCC 患者的生存良好相关，这可能导致该疾病的进展缓慢。
我们的研究发现，HBp/FOXO3/miRNA-30b-5p/MINPP1 轴通过糖酵解旁路促进 HBV 阳性 HCC 细胞的发展。我们还提出 miRNA-30b-5p/MINPP1 作为 HBV 阳性 HCC 早期诊断的新型生物标志物和抗肿瘤治疗的潜在药物靶点。
