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Abstract
Cholangiocarcinoma (CCA), a lethal malignancy of the biliary epithelium, is the second most common primary liver cancer. The poor prognosis of CCA is due to the high rate of tumour invasion and distant metastasis. We found that the RNA-binding protein LIN28B, a known regulator of microRNA biogenesis, stem cell maintenance, and oncogenesis, is expressed in a subpopulation of CCA patients. To further investigate the potential role of LIN28B in CCA pathogenesis, we studied the effect of LIN28B overexpression in the cholangiocyte cell line MMNK-1 and cholangiocarcinoma cell lines HuCCT-1 and KKU-214. Here, we show that enhanced LIN28B expression promoted cancer stem cell-like properties in CCA, including enhanced cell migration, epithelial-to-mesenchymal transition (EMT), increased cell proliferation and spheroid formation. Proteomic analysis revealed TGF-β-induced protein (TGFBI) as a novel LIN28B target gene, and further analysis showed upregulation of other components of the TGF-β signalling pathway, including TGF-β receptor type I (TGFBRI) expression and cytokine TGFB-I, II and III secretion. Importantly, the small molecule TGF-β inhibitor SB431542 negated the effects of LIN28B on both cell migration and clonogenic potential. Overexpression of TGFBI alone promoted cholangiocarcinoma cell migration and EMT changes, but not spheroid formation, suggesting that TGFBI partially contributes to LIN28B-mediated aggressive cell behaviour. These observations are consistent with a model in which TGF-β and LIN28B work together to form a positive feedback loop during cholangiocarcinoma metastasis and provide a therapeutic intervention opportunity.
Highlights
Cholangiocarcinoma (CCA) is a biliary tract cancer with one of the highest mortality rates among all cancers and has an increasing incidence rate worldwide [1]
transforming growth factor beta induced protein (TGFBI) noticeably increased the migration of MMNK-1 cells (Fig. 6b and Supplementary Fig. 3a) and HuCCT-1 cells
We demonstrated that part of this observation is due to LIN28B enhancing the TGF-β/epithelial-to-mesenchymal transition (EMT) programme
Summary
Cholangiocarcinoma (CCA) is a biliary tract cancer with one of the highest mortality rates among all cancers and has an increasing incidence rate worldwide [1]. Mechanisms proposed to be responsible for oncogenic transformation of LIN28 include derepression of let-7 targets such as cMyc, RAS and HMGA2 oncogenes [14,15,16] and let-7-independent translational control of genes that regulate the cell cycle and stemness, such as cyclin A, CDK4, and OCT4 [16]. In a mouse model of cholestasis-associated CCA, LIN28B expression was increased, suggesting that the LIN28 pathway may play a role in the pathogenesis of CCA [19]. TGF-β plays a role in cholangiocarcinoma metastasis and provide a examined known LIN28/let-7 target genes that regulate the cell novel target for therapeutic intervention for CCA. The expression of these genes was significantly increased in MMNK-1_LIN28B cells compared to control cells (Fig. 2b).
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