TMEM98 mRNA promotes proliferation and invasion of gastric cells by directly interacting with NF90 protein

Abstract

Transmembrane protein 98 (TMEM98) is a recently discovered gene, the inhibition of which has preliminarily been demonstrated to inhibit progression of several solid cancers in vitro. However, its involvement in tumorigenesis of gastric cancer (GC) has not been reported. Here, we aimed to explore the expression of TMEM98 in GC tissues and cell lines and to determine the role of TMEM98 in GC cell proliferation and invasion. TMEM98 was significantly upregulated in GC tissues, which was associated with low survival rate of GC patients. Interestingly, GC cell proliferation and invasion were promoted by TMEM98 messenger RNA (mRNA) upregulation and inhibited by TMEM98 mRNA downregulation, but not affected by TMEM98 protein. Using RNA‐binding protein immunoprecipitation assay and RNA pull‐down assay, we demonstrated that TMEM98 mRNA could directly bind with and upregulate nuclear factor 90 (NF90). Similarly, NF90 protein could not only enhance the stability of TMEM98 mRNA but antagonize the suppressive effect of TMEM98‐small interfering RNA on proliferation and invasion in MKN‐45 cells. Moreover, RNA pull‐down assay, with wild‐type (WT) and binding‐site‐mutated biotinylated TMEM98 mRNA transcripts, demonstrated that WT TMEM98 mRNA bound with NF90 protein through an 8‐nt motif at the last exon, but the motif mutation abolished the capacity of TMEM98 mRNA binding to NF90 protein. Furthermore, overexpression of the WT last exon of TMEM98 increased NF90 expression and cell proliferation/invasion expectedly, but overexpression of the mutated last exon had no obvious effect. In conclusion, TMEM98 mRNA enhanced the proliferation and invasion of GC cells by interacting with the NF90 protein.

Tumor-Suppressor Gene Transmembrane Protein 98 Promotes Proliferation and Inhibits Apoptosis in Ovarian Cancer

“…However, TMEM98 was overexpressed in hepatocellular carcinoma and was significantly associated with advanced stage and poor prognosis [16]. In those with cervical adenocarcinoma [17], lung cancer [18], gastric cancer [19], and head and neck carcinoma [20], TMEM98 was also overexpressed in tumors compared to the normal tissues. In the TNMplot database, there were also significant differences in the expression of TMEM98 in different tumors.…”

“…Li et al [20] also found that down-regulation of TMEM98 represses prolif-eration ability and migration ability of head neck cancer cells. In gastric cancer, Ao et al [19] showed that cell proliferation and invasion were promoted by upregulation of TMEM98 mRNA. In our study, we found the exact opposite function by si-TMEM98 in OC.…”

The transmembrane proteins (TMEM) and their role in cell proliferation, migration, invasion, and epithelial-mesenchymal transition in cancer

“…In the MKN-45 and SGC-790 cell lines, the expression of TMEM98 was reduced by a siRNA, and this led to a significant decrease in cell proliferation and invasion, in a dose-dependent manner of the siRNA. The overexpression of TMEM98 with a recombinant protein in MKN-45 and SGC-7901 cells showed that the effect on cell proliferation and invasion is mediated by the TMEM98 mRNA and not by mature protein since protein levels increased, however, without effect on cell viability and invasion ( 54 ). Computer analysis identified the TMEM98 mRNA target protein as the RNA-binding protein nuclear factor 90 (NF90) to which TMEM98 mRNA binds through an 8-nucleotide motif, but the underlying mechanism of this binding remains unclear, but, whether the cancer-promoting effect through TMEM98 mRNA ( 54 ).…”

“…Several reports have shown that some TMEM proteins have a specific role as oncogenes by promoting different processes in tumor cells as proliferation cell, migration, intravasation/extravasation, metastasis and modulation of the immune response ( 25 , 91 ). For example, in glioblastoma cells TMEM45A promoting cell proliferation, migration, and invasion ( 27 ) and TMEM98 in gastric cancer ( 54 ), among others. Some TMEM proteins have also been reported to favor epithelial-mesenchymal transition (EMT), such as TMEM45A in colorectal cancer ( 28 ).…”