TMEFF2: A New Target for Multiple Cancers

Transmembrane protein with an EGF-like and two Follistatin-like domains 2 (TMEFF2) is a 374-residue long type-I transmembrane proteoglycan which is proteolytically shed from the cell surface. The protein is involved in a range of functions including metabolism, neuroprotection, apoptosis, embryonic development, onco-suppression and endocrine function. TMEFF2 is methylated in numerous cancers, and an inverse correlation with the stage, response to therapy and survival outcome has been observed. Moreover, TMEFF2 methylation increases with breast, colon and gastric cancer progression. TMEFF2 is methylated early during oncogenesis in breast and colorectal cancer, and the detection of methylated free-circulating TMEFF2 DNA has been suggested as a potential diagnostic tool.

What is TMEFF2?

The Transmembrane protein with an EGF-like and two Follistatin-like domains 2 (TMEFF2) gene is located on chromosome 2q32-q33 and encodes a 374-residue long single polypeptide, type-I transmembrane proteoglycan. According to the HUGO gene nomenclature committee, the aliases of TMEFF2 include 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 reported functions of TMEFF2 span across a wide range of physiological and pathological spectra, ranging from corticotropin release hormone (CRH) stimulation in the anterior pituitary gland and providing neuroprotection by binding the amyloid β protein derivatives in Alzheimer's disease on one hand to triggering the JAK-STAT pathway in colorectal cancer and modulating one-carbon metabolism in prostate tissue on the other. The TMEFF2 promoter and its 5'-upstream CpG island are methylated in a number of cancers. TMEFF2 is a multidomain protein with its N-terminus harbouring a signal peptide followed by two follistatin-like domains, an EGF (epidermal growth factor)-like domain, a transmembrane portion and a short intracellular domain.

Fig. 1 Transmembrane protein with an EGF-like and two Follistatin-like domains 2 (TMEFF2) protein architecture.

The Role of TMEFF2 in Cancer Therapy

TMEFF2 in Prostate Cancer

TMEFF2 expression was markedly increased in prostate carcinoma vs. benign prostate hyperplasia and that its mRNA levels increased in higher-grade prostate cancers. These findings point towards an oncogenic role of TMEFF2 in prostate cancer. Such an inference is reinforced by several subsequent studies: for example, Bhaskar et al. reported that both protein and TMEFF2 mRNA levels increased significantly in prostate cancer compared to normal tissue. The authors also developed an antibody-drug conjugate (ADC) named Pr1-vcMMAE. Compared to the control ADC, Pr1-vcMMAE effectively reduced the tumour size in LNCap prostate cancer xenografts with minimal toxicity. The humanized version of ADC, hPr1-vcMMAE, gave similar results when used against the CWR22 prostate cancer xenografts.

TMEFF2 in Gastric and Colorectal Cancers

Further corroborating evidence on the onco-suppressive role of TMEFF2 came from studies in gastric and colorectal cancers. five TMEFF2 interacting proteins in AGS gastric cancer cells, including tyrosine-protein phosphatase non-receptor type 6 (SHP1), Ras GTPase-activating protein-binding protein 1 (G3BP1), heterogeneous nuclear ribonucleoprotein K (HNRPK), splicing factor 1 and ubiquitin carboxyl-terminal hydrolase 4 (USP4). The interaction of TMEFF2 with SHP1 in AGS and MKN45 gastric cancer cells resulted in cell cycle arrest, induction of apoptosis and a decrease in cell proliferation both in vitro and in vivo (xenograft models). This interaction between TMEFF2 and SHP1 was abolished upon deletion of the TMEFF2 intracellular domain. Moreover, no mutations were found in the TMEFF2 intracellular domain in gastric cancer patients. These findings corroborate the importance of the TMEFF2 intracellular domain as well as the fact that promoter methylation rather than mutation is the primary cause of TMEFF2 loss of function. The investigators also proposed that TMEFF2 had a role in maintaining genomic integrity as TMEFF2 knockdown in GES-1 gastric cancer cells led to an increase in DNA damage. DNA damage-related genes were found to be enriched in TMEFF2 overexpressing AGS cells and gastric tumours with high TMEFF2 expression levels.

In conclusion, TMEFF2 is methylated in several cancers and could potentially be used as both a prognostic and a diagnostic marker. TMEFF2 is expressed in many tissues, the highest levels being observed in brain and prostate. The oncogenic vs. onco-suppressive function of TEMFF2 is decided by numerous factors including cell type, expression level, proteolytic processing and posttranslational modification state. Thus, TMEFF2 is an intriguing protein with multifaceted functions, the physiological role of which remains to be elucidated.

Reference:

Masood, M.; et al. TMEFF2: A Transmembrane Proteoglycan with Multifaceted Actions in Cancer and Disease. Cancers. 2020, 12(12):3862.

Transfected Stable Cell Lines	Panoply™ Human TMEFF2 Knockdown Stable Cell Line	Panoply™ Human TMEFF2 Over-expressing Stable Cell Line
Premade Viral Particles	Human TMEFF2 adenoviral particles	Panoply™ Human TMEFF2 Over-expressing Stable Cell Line
Clones	Human TMEFF2 cDNA Clone (NM_016192.2)	Rat Tmeff2 cDNA Clone (NM_001108795.1)	TMEFF2 miRNA 3'UTR clone

* For research use only. Not intended for any clinical use.

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TMEFF2: A New Target for Multiple Cancers

What is TMEFF2?

The Role of TMEFF2 in Cancer Therapy

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