Molecular Pathogenesis and Regulation of the miR-29-3p-Family: Involvement of ITGA6 and ITGB1 in Intra-Hepatic Cholangiocarcinoma.
Molecular Pathogenesis and Regulation of the miR-29-3p-Family: Involvement of ITGA6 and ITGB1 in Intra-Hepatic Cholangiocarcinoma.
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DOI：
10.3390/cancers13112804
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发表时间：
2021-06-04
期刊：
影响因子：
5.2
通讯作者：
Ohtsuka T
中科院分区：
文献类型：
--
作者：
Hozaka Y;Seki N;Tanaka T;Asai S;Moriya S;Idichi T;Wada M;Tanoue K;Kawasaki Y;Mataki Y;Kurahara H;Ohtsuka T
即使在今天，也没有有效的靶向治疗肝内胆管癌（ICC）患者。阐明ICC的分子发病机制将有助于该病治疗策略的发展。在这项研究中，我们寻找miR-29- 3 p家族的作用及其与致癌途径的关联。有趣的是，ITGA 6和ITGB 1的异常表达直接受到miR-29- 3 p家族的调控，这些家族参与ICC中的多种致癌途径，并增强ICC细胞的恶性转化。此外，SP1是ITGA 6/ITGB 1的转录激活因子，受miR-29- 3 p家族调控。这些分子可能是ICC的新的治疗靶点。肝内胆管细胞癌（ICC）的侵袭性使其成为一种特别致命的实体瘤。寻找ICC的治疗靶点是开发有效治疗策略的重要挑战。我们之前的研究表明，miR-29- 3 p家族成员（miR-29 a-3 p，miR-29 b-3 p和miR-29 c-3 p）是控制多种癌症中许多致癌基因/途径的关键肿瘤抑制microRNA。在这项研究中，我们使用miR-29- 3 p家族作为起点寻找ICC的治疗靶点。我们对细胞增殖、迁移和侵袭的功能研究证实了miR-29- 3 p家族在ICC细胞中起肿瘤抑制因子的作用。此外，计算机模拟分析显示，“粘着斑”、“ECM受体”、“内吞作用”、“PI 3 K-Akt信号传导”和“Hippo信号传导”参与ICC细胞中的致癌途径。我们的分析集中在整合素-α6（ITGA 6）和整合素-β1（ITGB 1）的基因上，它们参与多种途径。ITGA 6和ITGB 1的过表达促进了ICC细胞的恶性转化。在ICC细胞中，ITGA 6和ITGB 1均受miR-29- 3 p家族的直接调控。有趣的是，ITGA 6/ITGB 1的表达受转录因子SP1的正控制，而SP1受miR-29- 3 p家族的负控制。miR-29- 3 p家族的下调增强了ICC细胞中SP1介导的ITGA 6/ITGB 1表达。基于microRNA的探索是一种有吸引力的策略，用于确定ICC的治疗靶点。
Even today, there are no effective targeted therapies for intrahepatic cholangiocarcinoma (ICC) patients. Clarifying the molecular pathogenesis of ICC will contribute to the development of treatment strategies for this disease. In this study, we searched for the role of the miR-29-3p-family and its association with oncogenic pathway. Interestingly, aberrant expression of ITGA6 and ITGB1 was directly regulated by the miR-29-3p-family which are involved in multiple oncogenic pathways in ICC, and enhanced malignant transformation of ICC cells. Furthermore, SP1 which is a transcriptional activator of ITGA6/ITGB1, is regulated by the miR-29-3p-family. These molecules may be novel therapeutic targets for ICC. The aggressive nature of intrahepatic cholangiocarcinoma (ICC) renders it a particularly lethal solid tumor. Searching for therapeutic targets for ICC is an essential challenge in the development of an effective treatment strategy. Our previous studies showed that the miR-29-3p-family members (miR-29a-3p, miR-29b-3p and miR-29c-3p) are key tumor-suppressive microRNAs that control many oncogenic genes/pathways in several cancers. In this study, we searched for therapeutic targets for ICC using the miR-29-3p-family as a starting point. Our functional studies of cell proliferation, migration and invasion confirmed that the miR-29-3p-family act as tumor-suppressors in ICC cells. Moreover, in silico analysis revealed that “focal adhesion”, “ECM-receptor”, “endocytosis”, “PI3K-Akt signaling” and “Hippo signaling” were involved in oncogenic pathways in ICC cells. Our analysis focused on the genes for integrin-α6 (ITGA6) and integrin-β1 (ITGB1), which are involved in multiple pathways. Overexpression of ITGA6 and ITGB1 enhanced malignant transformation of ICC cells. Both ITGA6 and ITGB1 were directly regulated by the miR-29-3p-family in ICC cells. Interestingly, expression of ITGA6/ITGB1 was positively controlled by the transcription factor SP1, and SP1 was negatively controlled by the miR-29-3p-family. Downregulation of the miR-29-3p-family enhanced SP1-mediated ITGA6/ITGB1 expression in ICC cells. MicroRNA-based exploration is an attractive strategy for identifying therapeutic targets for ICC.
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DOI：
10.1038/nrc3932
发表时间：
2015-06
期刊：
Nature reviews. Cancer
影响因子：
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Lin S;Gregory RI
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