METTL3 May Regulate Testicular Germ Cell Tumors Through EMT and Immune Pathways

Abstract

Testicular germ cell tumors (TGCTs) are highly prevalent in young men aged 20–40 years and are one of the most common lethal solid tumors in men of this age. Due to the current unclear mechanism of tumor development, there is a lack of effective treatment, and therefore in-depth research of the molecular mechanism of the occurrence and development of TGCT and the search for suitable and effective therapeutic targets and molecular markers are of great significance for achieving effective treatment. METTL3 is a very important methylase, which has been implicated in the progression of many cancers, but the role of METTL3 in TGCT has not been fully elucidated. In this article, we found that METTL3 expression was significantly downregulated in TGCT tissues, and patients with low expression levels had lower overall survival and relapse-free survival rates. After overexpressing METTL3, cell proliferation, invasion, and migration ability significantly increased, while influencing the expression of epithelial–mesenchymal transition (EMT)-related proteins. In addition, we observed that the expression level of METTL3 positively correlated with molecular markers and infiltration level of CD8+ and CD4+ T cells and natural killer cells. In sum, our findings identified that METTL3 can be used as an independent prognostic marker in patients with TGCT. METTL3 participates in the proliferation, migration, and invasion of TGCT cells by regulating the expression of EMT-related genes and may also play a role in activating the tumor immune response in TGCT.

The component of the m6A writer complex VIRMA is implicated in aggressive tumor phenotype, DNA damage response and cisplatin resistance in germ cell tumors

“…Indeed, these players have been implicated in several tumor models and in most stages of their development, from tumor initiation, to proliferation, invasion, metastatic dissemination, response/resistance to therapy and even modulation of the tumor microenvironment and phenomena like differentiation and epithelial-to-mesenchymal transition (EMT) [4,[41][42][43][44][45]. Few studies on TGCTs are available, though [10][11][12][13]. We hypothesize that owing to the intricate link of these tumors to embryonic and germ cell development [in which m 6 A is widely described as fundamental [18][19][20][46][47][48][49][50]], investigation of such alterations holds the promise of identifying putative clinically useful biomarkers of the disease [51] and novel therapeutic approaches for these patients [52,53].…”

“…This indicates that METTL3 contributes to cisplatin resistance in the seminoma phenotype, and supports an oncogenic role for this player. There have been however some conflicting findings regarding the role of METTL3 in TGCTs, with another study [12] analyzing in silico data and showing METTL3 to be downregulated in TGCT tissues and lower expression to confer inferior disease-free survival (suggestive of a tumor suppressor role). Nonetheless, the same authors found increased proliferation, migration and invasion (by regulating EMT genes) in vitro, upon overexpression of this factor (suggestive of an oncogenic role).…”

“…The field is expanding and, recently, research has been directed towards targeting these alterations therapeutically [9]. However, still few works have focused on testicular germ cell tumors (TGCTs) [10][11][12][13][14].…”

The m6A methyltransferase METTL3 regulates autophagy and sensitivity to cisplatin by targeting ATG5 in seminoma

“…In colorectal cancer, METTL3 promotes tumor metastasis through miR-1246/SPRED2/MAPK pathway (36). As for TGCTs, METTL3 can promote the proliferation, invasion, migration and EMT of TGCTs cell line (37). In this study, we found that the expression of METTL3 was increased in drug-resistant TCam-2 cells.…”

Targeting the RNA m6A modification for cancer immunotherapy

“…Abnormal expression of METTL3 in tumor cells affects the infiltration of immune cells. In testicular germ cell tumors (TGCT), METTL3 expression was significantly downregulated in TGCT tissues, and its level correlated positively with patient survival rates and levels of tumor-infiltrating CD8 + T cells, CD4 + T cells, and NK cells [ 69 ]. However, METTL3 was highly expressed in CRC tumor cells.…”