Role of laminin and cognate receptors in cholangiocarcinoma cell migration

Abstract

Extensive desmoplasia in cholangiocarcinoma (CCA) is associated with tumor aggressiveness, indicating a need for further understanding of CCA cell-matrix interaction. This study demonstrated laminin as the most potent attractant for CCA cell migration and the vast elevation of its receptor integrin β4 (ITGB4) in CCA cell lines. Besides, their high expressions in CCA tissues were correlated with lymphatic invasion and the presence of ITGB4 was also associated with short survival time. ITGB4 silencing revealed it as the receptor for laminin-induced HuCCA-1 migration, but KKU-213 utilized 37/67-kDa laminin receptor (LAMR) instead. These findings highlight the role of ITGB4 and LAMR in transducing laminin induction of CCA cell migration and the potential of ITGB4 as diagnostic and prognostic biomarkers for CCA.

Bioinformatics and qPCR analyses of laminins' cognate receptors in cholangiocarcinoma tissues reveal the integrin ITGB4 as a potential biomarke

“…Various RNA-sequencing and microarray databases are publicly available to explore differentially expressed genes involved in carcinogenesis and progression, opening the door for gaining valuable information for clinical applications. Laminin has recently been demonstrated to be the most potent inducer for CCA migration [10]. In the present study, an in silico analysis using two RNA sequencing (PCAWG, TCGA) databases and 10 microarray datasets (GEO database) was utilized to compare the expression of laminins' cognate receptors between CCA and adjacent noncancerous tissues.…”

“…On the contrary, integrin β4, having a restricted ligand binding capacity, interacts only with integrin α6. Accumulating data have showed the elevated expression of α6β4 integrin and its roles in aggressive phenotypes of various carcinomas including CCA [10,31]. Previously, we demonstrated the overexpression of integrin β4 in three (HuCCA-1, KKU-100, and KKU-213) of the four Thai patient-derived CCA cell lines compared with that of non-tumorigenic cholangiocyte MMNK-1, as well as the functions of integrin β4 as the main receptor in laminin-stimulated HuCCA-1 migration and adhesion [10].…”

“…Accumulating data have showed the elevated expression of α6β4 integrin and its roles in aggressive phenotypes of various carcinomas including CCA [10,31]. Previously, we demonstrated the overexpression of integrin β4 in three (HuCCA-1, KKU-100, and KKU-213) of the four Thai patient-derived CCA cell lines compared with that of non-tumorigenic cholangiocyte MMNK-1, as well as the functions of integrin β4 as the main receptor in laminin-stimulated HuCCA-1 migration and adhesion [10]. Given the diversity in dimerization of the β1 and β4 subunits and their upregulation in several human malignancies, the overexpression of these two subunits from in silico studies was confirmed in the CCA tissues of Thai patients using qPCR analysis.…”

“…Due to highly desmoplastic environment of CCA, deciphering the CCA cell-matrix interaction would not only provide a deep understanding of CCA progression, but also a better therapeutic intervention of this deadly disease. We previously showed that laminins, a family of cell-adhesive glycoproteins constituting to a major proportion of ECM proteins in basement membrane, were the most potent migrating attractors for CCA cell lines [10]. Laminins relay signals via multiple signal transduction pathways involving various components, viz.…”

“…Following the previous finding, integrin β4 was shown to be strongly expressed in CCA with correlation to lymphatic invasion and patients' survival. Moreover, integrin β4 was also responsible for lamininpromoted migration of integrin β4-overexpressing CCA cell lines [10]. However, the expression of other laminins' cognate receptors in CCA has not been well addressed yet.…”