Intrahepatic cholangiocarcinoma (iCCA) is a highly fatal malignant cancer worldwide. Elucidating the underlying molecular mechanism of iCCA progression is critical for the identification of new therapeutic targets. The present study explored the role of the miR-148a-GLUT1 axis in the progression of iCCA. The expression of GLUT1 was detected by using immunohistochemistry, western blot assays, and real-time polymerase chain reaction. The effects of GLUT1 on cell proliferation, invasion, and chemoresistance were investigated both in vitro and in vivo. A luciferase reporter assay was used to explore the effect of miR-148a on GLUT1 expression. GLUT1 was overexpressed in iCCA tissues. GLUT1 overexpression was associated with shorter overall and disease-free survival. Knockdown of GLUT1 reduced, while overexpression of GLUT1 promoted, the proliferation, motility, and invasiveness of iCCA cells in vitro and in vivo. Silencing GLUT1 significantly sensitized iCCA cells to gemcitabine in vitro and in vivo. GLUT1 was directly regulated by miR-148a, whose downregulation was associated with the proliferation, migration, and invasion of iCCA cells. WZB117, a GLUT1 inhibitor, inhibited tumor growth in an iCCA patient-derived xenograft model. These results indicate that downregulation of miR-148a levels results in GLUT1 overexpression in iCCA, leading to iCCA progression and gemcitabine resistance.

中文翻译：

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miR-148a-GLUT1轴失调促进了人肝内胆管癌的进展和化学耐药性。

肝内胆管癌（iCCA）是世界范围内致命性极高的恶性肿瘤。阐明iCCA进展的潜在分子机制对于鉴定新的治疗靶标至关重要。本研究探讨了miR-148a-GLUT1轴在iCCA进展中的作用。GLUT1的表达通过免疫组织化学，Western blot分析和实时聚合酶链反应检测。在体外和体内研究了GLUT1对细胞增殖，侵袭和化学抗性的影响。萤光素酶报告基因测定用于探讨miR-148a对GLUT1表达的影响。GLUT1在iCCA组织中过表达。GLUT1过表达与较短的总体生存期和无病生存期有关。GLUT1的敲低减少，而GLUT1的过表达促进，增殖，iCCA细胞在体外和体内的活力和侵袭性。沉默GLUT1可在体内外使iCCA细胞对吉西他滨敏感。GLUT1由miR-148a直接调控，其下调与iCCA细胞的增殖，迁移和侵袭有关。WZB117，一种GLUT1抑制剂，在来自iCCA患者的异种移植模型中抑制肿瘤的生长。这些结果表明，miR-148a水平的下调导致iCCA中GLUT1的过度表达，从而导致iCCA进展和吉西他滨耐药。GLUT1抑制剂可抑制来自iCCA患者的异种移植模型中的肿瘤生长。这些结果表明，miR-148a水平的下调导致iCCA中GLUT1的过度表达，从而导致iCCA进展和吉西他滨耐药。GLUT1抑制剂可抑制来自iCCA患者的异种移植模型中的肿瘤生长。这些结果表明，miR-148a水平的下调导致iCCA中GLUT1的过度表达，从而导致iCCA进展和吉西他滨耐药。