Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany.
Department of Immunology, Genetics and Pathology, Uppsala University, 75108 Uppsala, Sweden.
Cells. 2021 Oct 18;10(10):2787. doi: 10.3390/cells10102787.
In the rat, the pancreatic islet transplantation model is an established method to induce hepatocellular carcinomas (HCC), due to insulin-mediated metabolic and molecular alterations like increased glycolysis and de novo lipogenesis and the oncogenic AKT/mTOR pathway including upregulation of the transcription factor Carbohydrate-response element-binding protein (ChREBP). ChREBP could therefore represent an essential oncogenic co-factor during hormonally induced hepatocarcinogenesis.
Pancreatic islet transplantation was implemented in diabetic C57Bl/6J (wild type, WT) and ChREBP-knockout (KO) mice for 6 and 12 months. Liver tissue was examined using histology, immunohistochemistry, electron microscopy and Western blot analysis. Finally, we performed NGS-based transcriptome analysis between WT and KO liver tumor tissues.
Three hepatocellular carcinomas were detectable after 6 and 12 months in diabetic transplanted WT mice, but only one in a KO mouse after 12 months. Pre-neoplastic clear cell foci (CCF) were also present in liver acini downstream of the islets in WT and KO mice. In KO tumors, glycolysis, de novo lipogenesis and AKT/mTOR signalling were strongly downregulated compared to WT lesions. Extrafocal liver tissue of diabetic, transplanted KO mice revealed less glycogen storage and proliferative activity than WT mice. From transcriptome analysis, we identified a set of transcripts pertaining to metabolic, oncogenic and immunogenic pathways that are differentially expressed between tumors of WT and KO mice. Of 315 metabolism-associated genes, we observed 199 genes that displayed upregulation in the tumor of WT mice, whereas 116 transcripts showed their downregulated expression in KO mice tumor.
The pancreatic islet transplantation model is a suitable method to study hormonally induced hepatocarcinogenesis also in mice, allowing combination with gene knockout models. Our data indicate that deletion of ChREBP delays insulin-induced hepatocarcinogenesis, suggesting a combined oncogenic and lipogenic function of ChREBP along AKT/mTOR-mediated proliferation of hepatocytes and induction of hepatocellular carcinoma.
在大鼠中，胰岛移植模型是诱导肝细胞癌（HCC）的一种成熟方法，这是由于胰岛素介导的代谢和分子改变，如增加糖酵解和从头脂肪生成，以及致癌 AKT/mTOR 通路，包括转录因子碳水化合物反应元件结合蛋白（ChREBP）的上调。因此，ChREBP 可能是激素诱导的肝癌发生过程中必不可少的致癌协同因子。
将胰岛移植到糖尿病 C57Bl/6J（野生型，WT）和 ChREBP 敲除（KO）小鼠中，持续 6 和 12 个月。使用组织学、免疫组织化学、电子显微镜和 Western blot 分析检查肝组织。最后，我们对 WT 和 KO 肝肿瘤组织进行了基于 NGS 的转录组分析。
在糖尿病移植 WT 小鼠中，6 个月和 12 个月后可检测到 3 个肝细胞癌，但在 12 个月的 KO 小鼠中仅检测到 1 个。在 WT 和 KO 小鼠的胰岛下游肝腺泡中也存在前癌性透明细胞灶（CCF）。与 WT 病变相比，KO 肿瘤中的糖酵解、从头脂肪生成和 AKT/mTOR 信号转导明显下调。糖尿病、移植 KO 小鼠的肝外组织的糖原储存和增殖活性低于 WT 小鼠。从转录组分析中，我们确定了一组与代谢、致癌和免疫相关的途径的转录本，这些转录本在 WT 和 KO 小鼠的肿瘤之间存在差异表达。在 315 个与代谢相关的基因中，我们观察到 199 个基因在 WT 小鼠的肿瘤中上调，而 116 个基因在 KO 小鼠的肿瘤中下调。
胰岛移植模型是研究激素诱导的肝癌发生的一种合适方法，也适用于小鼠，允许与基因敲除模型相结合。我们的数据表明，ChREBP 的缺失延迟了胰岛素诱导的肝癌发生，表明 ChREBP 具有致癌和脂肪生成功能，与 AKT/mTOR 介导的肝细胞增殖和肝细胞癌的诱导有关。
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