Transgelin-2 (TAGLN2) as a potential therapeutic target of gemcitabine resistant-biliary tract cancer

Abstract

Purpose Transgelin-2 (TAGLN2) is highly expressed in biliary tract cancer (BTC) associated cancer stem cells (CSC) compared with normal bile duct cells by genetic analysis. However, the functional role of TAGLN2 has not been determined. We investigated that the role of TAGLN2 in malignant behaviors and chemoresistance in BTC cells. Materials and Methods The TAGLN2 knockdown cell line was established by transfection of small hairpin TAGLN2 (shTAGLN2) into human biliary tract cancer cell line, SNU-1196 and SNU-308, and the cell proliferation, migration, invasion, and molecular characteristics were assessed in vitro and in vivo. The TAGLN2 expression on multiple human organ tissues including BTC was investigated by immunohistochemistry (IHC). Small interfering TAGLN2 (siTAGLN2) was transfected into gemcitabine-resistant BTC cells, and cell viability was assessed in chemotherapeutic agents including gemcitabine, 5-FU, cisplatin, carboplatin, oxaliplatin, irinotecan, etoposide, and erlotinib. Results Suppression of TAGLN2 expression decreased cellular proliferation, migration, and invasion in shTAGLN2/SNU-1196 cells. A significant reduction of tumorigenic potential of shTAGLN2/SNU-1196 cells was observed in vitro and in vivo. Western blotting revealed decreased expression of CSC markers such as c-met, Nanog, pAKT and AKT, and mesenchymal markers such as N-cadherin, Snail, and JAG2, but an increase in the epithelial molecule, Occludin in shTAGLN2/SNU-1196 cells. TAGLN2 was rarely expressed in most of the normal human organs tissues, whereas strong expression was noted in BTC tissue. However, there was no significant association of tumor staging, differentiation, and prognosis with the level of TAGLN2 expression. Suppression of TAGLN2 in SNU-1196/GR cells by siTAGLN2 transfection increased drug sensitivity to antimetabolites, gemcitabine, and 5-FU. Conclusion TAGLN2 plays functional roles in the progression of BTC, and CSC markers and mesenchymal markers were downregulated in TAGLN2 suppressed BTC cells. Our data suggest that chemosensitivity may be improved by suppression of TAGLN2 in gemcitabine-resistant BTC cells.