The multi-faceted role of TGFBR3 deregulation in oral cancer progression

Abstract

TGF-β type III receptor (TGFBR3) a co-receptor for TGF-β family members is required for the high-affinity binding of ligands to their receptors to initiate their cellular function More and more studies showed an opposing role of TGFBR3 tumor suppressor or oncogene in different cancer types However the exact role of TGFBR3 and the responsible mechanism in oral cancer remains to be characterized By using immunohistochemical staining and real-time PCR we found a down-regulation of TGFBR3 in oral cancer tissues when compared to their adjacent normal counterparts Low TGFBR3 expression patients tend to have poor clinical outcome compared with high expression patients Furthermore promoter methylation and TGF-β1 expression were involved in the decrease of TGFBR3 To examine the role of TGFBR3 in oral cancer cells we not only stably expressed shRNAs specific to TGFBR3 but also overexpressed TGFBR3 respectively in oral cancer cells TGFBR3 overexpression decreased cell migration invasion and metastasis Oral cancer cells with down-regulated TGFBR3 expression exhibited increased migration and invasion compared with control cells TGFBR3 functions as a sink for TGF-β signaling The cytoplasmic domain of TGFBR3 had a role in TGFBR3-mediated inhibition of migration and invasion through GIPC1 protein Moreover the conditioned medium from TGFBR3-overexpressing cancer cells also harbored tumor suppressive effects both on tumor cells and stromal cells By using cytokine array we found angiogenin could potentially serve as a downstream effector for TGFBR3-mediated tumor suppression Moreover the increased expression of angiogenin in TGFBR3-overexpressing cancer cells might depend on SMAD4 These data indicated the TGFBR3 act as a tumor suppressor in oral carcinogenesis This study should facilitate the possibility of using TGFBR3-mediated tumor suppression for oral cancer treatment

Date of Award	2019
Original language	English
Supervisor	Li-Wha Wu (Supervisor)