Role of Transmembrane 4 L Six Family 1 in the Development and Progression of Cancer.

Fangmei Fu,Zugui Li,Qi Zhao,Xudong Yang,Hao Zhang,Kexin Zhang,Shiwu Zhang,Minying Zheng

doi:10.3389/fmolb.2020.00202

Abstract

Transmembrane 4 L six family 1 (TM4SF1) is a protein with four transmembrane domains that belongs to the transmembrane 4 L six family members (TM4SFs). Structurally, TM4SF1 consists of four transmembrane domains (TM1–4), N- and C-terminal intracellular domains, two extracellular domains, a smaller domain between TM1 and TM2, and a larger domain between TM3 and TM4. Within the cell, TM4SF1 is located at the cell surface where it transmits extracellular signals into the cytoplasm. TM4SF1 interacts with tetraspanins, integrin, receptor tyrosine kinases, and other proteins to form tetraspanin-enriched microdomains. This interaction affects the pro-migratory activity of the cells, and thus it plays important roles in the development and progression of cancer. TM4SF1 has been shown to be overexpressed in many malignant tumors, including gliomas; malignant melanomas; and liver, prostate, breast, pancreatic, bladder, colon, lung, gastric, ovarian, and thyroid cancers. TM4SF1 promotes the migration and invasion of cancer cells by inducing epithelial-mesenchymal transition, self-renewal ability, tumor angiogenesis, invadopodia formation, and regulating the related signaling pathway. TM4SF1 is an independent prognostic indicator and biomarker in several cancers. It also promotes drug resistance, which is a major cause of therapeutic failure. These characteristics make TM4SF1 an attractive target for antibody-based immunotherapy. Here, we review the many functions of TM4SF1 in malignant tumors, with the aim to understand the interaction between its expression and the biological behaviors of cancer and to supply a basis for exploring new therapeutic targets.

Highlights

Transmitting signals between the extracellular and intracellular microenvironments is a fundamental function of the plasma membrane
SIRT1 inhibits the cell cycle and is an important upstream target of forkhead transcription factor 3a (FOXO3a) that can downregulate cyclin D1 (Schmidt et al, 2002). These findings indicate that Transmembrane 4 L six family 1 (TM4SF1) can inhibit apoptosis through an reactive oxygen species (ROS)-related pathway
TM4SF1 was shown to enhance the expression of Yes-associated protein (YAP) and strengthened YAP-transcriptional enhancer activator domain (TEAD) interaction to regulate the progression of malignant tumor cells (Fu et al, 2020)

Summary

Introduction

Transmitting signals between the extracellular and intracellular microenvironments is a fundamental function of the plasma membrane. Numerous studies have shown that TM4SF1 plays an indispensable role in promoting cancer cell proliferation and migration through a series of signaling pathways (Figure 2). Another study showed that decreased TM4SF1 expression enhanced the migration and invasion of pancreatic tumor cells in vitro (Zheng B. et al, 2015).

Results

Conclusion