Introduction
TMEFF2 (transmembrane protein with EGF-like and two follistatin-like domains 2) is a protein that has garnered significant attention in recent years due to its potential role in cancer biology. TMEFF2 is known for its involvement in various physiological processes, including cellular signaling and development. However, its dysregulation has been implicated in the progression of several types of cancer, making it a subject of intense study.
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The study of TMEFF2 involves understanding its expression patterns, mechanisms of regulation, and its functional role in different tissues and cancer types. One critical aspect of TMEFF2 research is the investigation of its promoter methylation status, which can influence its expression and, consequently, its role in cancer development and progression.
Fig. 1 Transmembrane protein with an EGF-like and two Follistatin-like domains 2 (TMEFF2) protein architecture (Masood M., et al. 2020).
Identification and Characterization
TMEFF2 is a type I transmembrane protein characterized by the presence of an epidermal growth factor (EGF)-like domain and two follistatin-like domains. It was first identified through its expression in the brain and prostate, suggesting a role in neuroendocrine tissues. The gene encoding TMEFF2 is located on chromosome 2q32-q33. The HUGO Gene Nomenclature Committee has recognized multiple aliases for TMEFF2, including HPP1, tomoregulin (TR), transmembrane protein TENB2 (TENB2), cancer/testis antigen family 120, member 2 (CT120.2), and transmembrane protein containing EGF and follistatin domains (TPEF).
The structure of TMEFF2 includes an N-terminal signal peptide, followed by two follistatin-like domains, an epidermal growth factor (EGF)-like domain, a transmembrane portion, and an intracellular domain. TMEFF2's structure, with its EGF-like and follistatin-like domains, hints at its potential involvement in signaling pathways that regulate cell growth, differentiation, and survival.
TMEFF2 Promoter Methylation in Cancer
Epigenetic modifications, such as DNA methylation, play a crucial role in regulating gene expression. In cancer, aberrant DNA methylation patterns can lead to the silencing of tumor suppressor genes or the activation of oncogenes. TMEFF2 promoter methylation has been a focal point in understanding its dysregulation in cancer.
TMEFF2 promoter methylation plays a crucial role in various cancers, affecting its expression and contributing to tumor progression. Studies indicate that TMEFF2 harbors a CpG island in its promoter region, where hypermethylation is observed in cancer tissues compared to normal mucosa. This hypermethylation correlates with reduced mRNA expression of TMEFF2. Treatment with DNA methyltransferase inhibitors restores TMEFF2 expression, confirming methylation as a primary mechanism of gene silencing. The methylation status of TMEFF2 correlates with cancer stages and patient outcomes in breast, prostate, lung, bladder, colon, rectal, gastric, ovarian, and other cancers. Furthermore, TMEFF2 methylation is detectable not only in cancer tissues but also in adjacent normal tissues and blood, suggesting its potential as a diagnostic and prognostic biomarker. Additionally, other mechanisms like histone deacetylase-mediated silencing have been implicated in TMEFF2 downregulation in colorectal cancer, highlighting its complex regulatory network in cancer biology.
TMEFF2 in Prostate Cancer
The role of TMEFF2 in prostate cancer remains contentious with studies presenting contrasting viewpoints on its function. While some studies suggest an oncogenic role, indicating increased expression in prostate carcinoma and enhanced proliferation in xenograft models, others propose an onco-suppressive function. Evidence supporting the latter includes reduced expression in androgen-independent prostate cancer cells and inhibitory effects on cell proliferation upon ectopic expression. Moreover, TMEFF2's expression dynamics in response to androgen treatment further complicate its characterization, suggesting it may act differently depending on androgen levels. Mechanistic insights into TMEFF2's activities reveal its involvement in stress responses and interaction with ADAM proteases, leading to ectodomain shedding that can influence cell proliferation. The presence of specific protease substrates and regulatory motifs in TMEFF2 also suggests context-dependent roles, influencing its potential as a therapeutic target or biomarker. Overall, the contradictory findings underscore the complexity of TMEFF2's role in prostate cancer biology, warranting further investigation to resolve its dual nature and therapeutic implications.
TMEFF2 in Gastric and Colorectal Cancers
TMEFF2 exhibits a confirmed onco-suppressive role in gastric and colorectal cancers, as supported by recent studies. Sun et al. demonstrated a significant decrease in TMEFF2 levels across various stages of gastric cancer, correlating with promoter methylation and poorer patient outcomes. Interaction studies in AGS cells identified several proteins binding to TMEFF2, including SHP1, G3BP1, HNRPK, splicing factor 1, and USP4. Notably, TMEFF2's interaction with SHP1 induced cell cycle arrest, apoptosis, and reduced proliferation in vitro and in xenografts, dependent on its intracellular domain integrity. In gastric cancer patients, no mutations affecting this domain were identified, highlighting promoter methylation as the primary mechanism of TMEFF2 downregulation rather than genetic mutations. Further investigations suggested TMEFF2's role in genomic stability, evidenced by increased DNA damage upon its depletion in gastric cancer cells.
In colorectal cancer, TMEFF2's onco-suppressive actions were elucidated by Shibata's group. TMEFF2 induced apoptosis and reduced proliferation in HCT-116 cells through STAT1 pathway activation. Microarray analysis of TMEFF2-stable HCT-116 cells revealed significant upregulation of interferon-inducible genes, emphasizing its role in immune response modulation. Additionally, TMEFF2 overexpression promoted STAT1 and STAT2 phosphorylation and nuclear localization, mediated by upregulated JAK1 and JAK2 kinases. Moreover, TMEFF2's shedding by ADAM17 was implicated in its onco-suppressive functions, linking proteolytic processing to its regulatory roles in colorectal cancer progression.
Conclusion
Although the role of TMEFF2 in different cancers exhibits complexity and contradictions, overall literature suggests that its anti-cancer function predominates in most cases. However, two factors need to be considered when studying TMEFF2. Firstly, TMEFF2 exhibits low expression levels with high variability both within and between tissues, impacting data interpretation in tissue-based assays. Secondly, experimental outcomes in cell line studies are influenced by the extent and duration of TMEFF2 modulation. Addressing these aspects enhances consistency and reproducibility across studies. Additionally, exploring TMEFF2's phosphorylation and glycosylation, which are poorly understood, could unveil further insights into its functional diversity and potential as a diagnostic and prognostic marker in various cancers.
References
- Masood M., et al. TMEFF2: A transmembrane proteoglycan with multifaceted actions in cancer and disease. Cancers. 2020, 12(12): 3862.
- Sun T., et al. TMEFF2 deregulation contributes to gastric carcinogenesis and indicates poor survival outcome. Clinical Cancer Research. 2014, 20(17): 4689-4704.
- Elahi A., et al. HPP1‐mediated tumor suppression requires activation of STAT1 pathways. International Journal of Cancer. 2008, 122(7): 1567-1572.
- Hernandez J. M., et al. The tumor suppressive effects of HPP1 are mediated through JAK-STAT-interferon signaling pathways. DNA and Cell Biology. 2015, 34(8): 541-549.
- Elahi A., et al. Hpp1 ectodomain shedding is mediated by Adam17 and is necessary for tumor suppression in colon cancer. Journal of Surgical Research. 2020, 254: 183-190.
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