Understanding the Complex Role of Transmembrane Proteins (TMEMs) in Cancer

Introduction

Transmembrane proteins (TMEMs) are a type of protein that spans the entire width of the lipid bilayer to which it is permanently anchored. Many TMEMs function as channels to permit the transport of specific substances across the biological membranes. TMEMs are present in many cell types and fulfill important physiological functions such as in immune response, protein glycosylation, and tissue development and differentiation. Furthermore, differential regulation of the expression of TMEMs has been observed in many cancers, and some of these proteins are even used as prognostic biomarkers.

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TMEMs as Tumor Suppressors

Transmembrane proteins play crucial roles in maintaining cellular homeostasis and regulating various physiological processes. Some members of the TMEM family have been identified as tumor suppressors, whose downregulation in cancer tissues is associated with adverse outcomes. One such example is TMEM25, a member of the immunoglobulin superfamily implicated in immune response, growth factor signaling, and cell adhesion. Studies have shown that TMEM25 mRNA expression is significantly reduced in colorectal adenocarcinoma and breast tumors, correlating with hypermethylation of specific CpG sites in the gene's 5' UTR region. This downregulation has been linked to poorer overall survival, emphasizing TMEM25's potential as a biomarker for favorable prognosis in certain cancers.

Another noteworthy TMEM with tumor suppressor properties is TMEM7, predominantly expressed in the liver. Its downregulation in hepatocellular carcinoma has been observed in both cell lines and primary tumor samples. The loss of TMEM7 expression is associated with chromosomal deletions common in cancer cells, and its restoration has been shown to inhibit tumor growth in vivo. These findings underscore the role of TMEM7 as a potential tumor suppressor in hepatocellular carcinoma.

Recent studies have identified TMEM176A as a tumor suppressor in esophageal squamous cell carcinoma and colorectal cancer. Methylation of the TMEM176A promoter is prevalent in these cancers, leading to decreased expression. Restoration of TMEM176A expression inhibits cell invasion, and migration, and induces apoptosis, suggesting its role as a crucial regulator of tumor progression.

TMEM97, also known as MAC30, has exhibited a dual role, acting as a potential tumor suppressor in pancreatic and prostate cancers while being overexpressed in other cancer types. In pancreatic cancer, reduced TMEM97 expression is associated with pre-neoplastic lesions, suggesting its role as a tumor suppressor. However, in breast, gastric, colon, epithelial ovarian, and non-small cell lung cancers (NSCLC), TMEM97 overexpression correlates with poor prognosis and tumor aggressiveness. This duality emphasizes the need for a nuanced understanding of TMEMs in different cancer contexts.

TMEMs Involved in Tumor Growth

While some TMEMs act as tumor suppressors, others contribute to tumor growth and progression. TMEM48, localized to nuclear pore complexes, is implicated in non-small cell lung carcinoma (NSCLC). Overexpression of TMEM48 in NSCLC tissues is associated with advanced tumor stage, lymph node metastasis, increased tumor size, and shorter survival. This suggests that TMEM48 may serve as a prognostic factor for NSCLC, emphasizing its role in tumor growth.

TMEM45A, predominantly expressed in the trans-Golgi apparatus, is overexpressed in various cancers, including breast, liver, renal, glioma, head and neck, ductal, and ovarian cancers. Higher expression of TMEM45A is correlated with lower overall survival in breast cancer and cervical lesions, indicating its potential as a biomarker for cancer aggressiveness.

TMEM16A, a calcium-activated chloride channel, is upregulated in several cancers, including head and neck squamous cell carcinoma (HNSCC), esophageal, breast, and gastric cancers. In HNSCC, higher TMEM16A expression is associated with poor prognosis, emphasizing its role as a negative prognostic factor. In colorectal cancer, TMEM16A knockdown inhibits cell proliferation, migration, and invasion, suggesting its involvement in tumor growth and metastasis.

TMEM88, an intriguing TMEM protein, interacts with components of the Wnt signaling pathway and demonstrates dual roles in cancer. When localized to the cell membrane, TMEM88 acts as a tumor suppressor, inhibiting the canonical Wnt pathway and suppressing proliferation, migration, and invasion in NSCLC and breast cancer. However, when cytosolic, TMEM88 enhances tumor aggressiveness, promoting metastasis and poor prognosis in NSCLC and triple-negative breast cancer.

Fig. 1 Schematic representation of the involvement of several TMEMs in tumor growth through the TGF-β signaling pathway (Schmit K., Michiels C. 2018).

TMEMs in Chemoresistance

In addition to their roles in tumor growth, TMEMs have been implicated in chemoresistance, a significant challenge in cancer treatment. Understanding the molecular mechanisms underlying chemoresistance is crucial for developing effective therapeutic strategies. TMEM14A, TMEM97, and TMEM16A have been identified as key players in modulating chemoresistance in various cancers.

TMEM14A, overexpressed in ovarian cancer, influences cell proliferation and invasion. Knockdown of TMEM14A sensitizes ovarian cancer cells to chemotherapy, suggesting its potential role in chemoresistance. The precise mechanisms through which TMEM14A contributes to chemoresistance warrant further investigation.

TMEM97, known for its role in tumor growth, has also been associated with chemoresistance. Studies in glioma and gastric cancer cells reveal that TMEM97 silencing inhibits cell proliferation, migration, and invasion while enhancing chemosensitivity. The involvement of TMEM97 in chemoresistance highlights its multifaceted role in cancer progression.

TMEM16A, implicated in colorectal cancer and gastric cancer, has been linked to chemoresistance. Its knockdown in colorectal cancer cells leads to decreased cell proliferation, migration, and invasion, suggesting a potential role in sensitizing cells to chemotherapy. In gastric cancer, TMEM16A expression correlates with tumor stage and negatively impacts patient survival, indicating its potential as a therapeutic target to overcome chemoresistance.

Conclusion

The intricate involvement of TMEMs in cancer spans a spectrum of roles, from acting as tumor suppressors to contributors to tumor growth and even players in chemoresistance. The dual nature of certain TMEMs, such as TMEM97 and TMEM88, highlights the complexity of their functions in different cancer types and stages. Unraveling the molecular mechanisms underlying these roles is essential for developing targeted therapies and improving patient outcomes.

As research advances, further exploration of TMEMs and their intricate interactions within cellular pathways will likely uncover novel therapeutic targets and diagnostic markers. The dynamic landscape of TMEMs in cancer underscores the importance of personalized medicine approaches, where treatment strategies can be tailored based on the specific molecular characteristics of individual tumors. The journey towards decoding the full extent of TMEM involvement in cancer continues, holding promise for more effective and precise cancer therapies in the future.

References

1. Herrena-Quiterio G. A.; Encarnacion-Guevara S. The transmembrane proteins (TMEM) and their role in cell proliferation, migration, invasion, and epithelial-mesenchymal transition in cancer. Frontiers in Oncology. 2023, 13: 1244740.
2. Schmit K.; Michiels C. TMEM proteins in cancer: a review. Frontiers in Pharmacology. 2018, 9: 1345.