TMEM Proteins in Cancer: A Review

Abstract

A transmembrane protein (TMEM) is a type of protein that spans biological membranes. Many of them extend through the lipid bilayer of the plasma membrane but others are located to the membrane of organelles. The TMEM family gathers proteins of mostly unknown functions. Many studies showed that TMEM expression can be down- or up-regulated in tumor tissues compared to adjacent healthy tissues. Indeed, some TMEMs such as TMEM48 or TMEM97 are defined as potential prognostic biomarkers for lung cancer. Furthermore, experimental evidence suggests that TMEM proteins can be described as tumor suppressors or oncogenes. TMEMs, such as TMEM45A and TMEM205, have also been implicated in tumor progression and invasion but also in chemoresistance. Thus, a better characterization of these proteins could help to better understand their implication in cancer and to allow the development of improved therapy strategies in the future. This review gives an overview of the implication of TMEM proteins in cancer.

Keywords: TMEM proteins; biomarkers; cancer; chemoresistance; oncogenes; tumor suppressors.

FIGURE 1

Schematic representation of the involvement of several TMEMs in tumor growth through the TGF-β signaling pathway. The activation of TGF-β signaling pathway has been implicated in many cellular processes and in tumor growth. This activation is induced by its ligand which then activates the phosphorylation of serine/threonine residues and triggers phosphorylation of the intracellular effectors, SMADs (blue). TGF-β receptors can also activate Smad-independent pathways (pink). In early stage TGF-β plays a tumor suppressor role whereas, in advanced stage, cancer cells benefit from TGF-β to initiate proliferation, invasion and metastasis dissemination. It seems that several TMEM proteins are involved in tumor growth through TGF-β activation in order to facilitate malignant progression and EMT progression. The stars represent the effectors deregulated by TMEMs.

FIGURE 2

Schematic representation of the chemoresistance mechanisms conferred by TMEM proteins. The chemoresistance can be due to an adaptation of the cancer cells themselves (mutations, DNA methylation, proteins, translocation…) but can also be provided from the interactions with the microenvironment. Some of these chemoresistance mechanisms involve TMEM proteins. (1) Hypoxia leads to HIF-1α stabilization and to the expression of several target genes such as TMEM45A. (2) Methylation or acetylation of promoters leads to the transcriptional regulation of genes such as TMEM88. (3) The increase in TMEM205 expression and its translocation modify its partners. (4) The immune system induces the expression of several genes such as TMEM98.