TMEM158 functions as an oncogene and promotes lung adenocarcinoma progression through the PI3K/AKT pathway via interaction with TWIST1.

Lung adenocarcinoma (LUAD) is a common and deadly form of lung cancer, with high rates of metastasis and unsatisfactory clinical outcomes. Herein, we examined the influence of TMEM158 on the LUAD progression. A combination of bioinformatic analyses was used to assess the TMEM158 expression pattern, prognostic implications, and potential function in LUAD. The levels of TMEM158 and TWIST1 were evaluated in clinical samples from LUAD patients using Western blot analysis and qRT-PCR. To discover the function and underlying molecular pathways of TMEM158 in LUAD, we employed a combination of experimental approaches in vitro, such as flow cytometry analysis and colony formation, Co-IP, CCK-8, Transwell, and wound-healing assays. Elevated expression of TMEM158 in LUAD is associated with increased cancer aggressiveness and a poor prognosis. In vitro experiments demonstrated that high levels of TMEM158 promote cell proliferation, progression through the cell cycle, migration, and invasion while suppressing apoptosis. Knockdown of TMEM158 produced opposite effects. The underlying mechanism involves TMEM158 and TWIST1 directly interacting, stimulating the PI3K/AKT signaling pathway in LUAD cells. This investigation emphasizes the molecular functions of TMEM158 in LUAD progression and proposes targeting it as a promising treatment approach for managing LUAD.

Systematic pan-cancer analysis identifies transmembrane protein 158 as a potential therapeutic, prognostic and immunological biomarker.

The purpose of this study was to investigate the expression significance, predictive value, immunologic function, and biological role of transmembrane protein 158 (TMEM158) in the development of pan-cancer. To achieve this, we utilized data from multiple databases, including TCGA, GTEx, GEPIA, and TIMER, to collect gene transcriptome, patient prognosis, and tumor immune data. We evaluated the association of TMEM158 with patient prognosis, tumor mutational burden (TMB), and microsatellite instability (MSI) in pan-cancer samples. We performed immune checkpoint gene co-expression analysis and gene set enrichment analysis (GSEA) to better understand the immunologic function of TMEM158. Our findings revealed that TMEM158 was significantly differentially expressed between most types of cancer tissues and their adjacent normal tissues and was associated with prognosis. Moreover, TMEM158 was significantly correlated with TMB, MSI, and tumor immune cell infiltration in multiple cancers. Co-expression analysis of immune checkpoint genes showed that TMEM158 was related to the expression of several common immune checkpoint genes, especially CTLA4 and LAG3. Gene enrichment analysis further revealed that TMEM158 was involved in multiple immune-related biological pathways in pan-cancer. Overall, this systematic pan-cancer analysis suggests that TMEM158 is generally highly expressed in various cancer tissues and is closely related to patient prognosis and survival across multiple cancer types. TMEM158 may serve as a significant predictor of cancer prognosis and modulate immune responses to various types of cancer.

TMEM158 promotes pancreatic cancer aggressiveness by activation of TGFß1 and PI3K/AKT signaling pathway.

Pancreatic cancer (PC) is one of the most deadly digestive cancers world-wide, with a dismal five-year survival rate of <8%. Upregulation of transmembrane protein 158 (TMEM158) is known to facilitate the progression of several carcinomas. However, little is known concerning the potential roles of TMEM158 in PC. Herein, we first found that TMEM158 was significantly upregulated in PC samples as well as PC cell lines. The overexpression of TMEM158 was significantly correlated with advanced clinicopathologic features (including tumor size, TNM stage, and blood vessel invasion) and poorer prognosis of patients with PC in clinic. Evidenced based on a series of loss- and gain-of-function assays uncovered that TMEM158 enhanced PC cell proliferation, migration, and invasion by stimulating the progression of cell cycle, epithelial-mesenchymal transition, and MMP-2/9 production. Furthermore, mechanism-related investigations disclosed that activation of TGFß1 and PI3K/AKT signal might be responsible for TMEM158-triggered PC aggressiveness. Collectively, TMEM158 was upregulated in PC and promoted PC cell proliferation, migration, and invasion through the activation of TGFß1 and PI3K/AKT signaling pathways, highlighting its potential as a tumor promoter and a therapeutic target for PC.

Illustrating the biological functions and diagnostic value of transmembrane protein family members in glioma.

Background: It is well-established that patients with glioma have a poor prognosis. Although the past few decades have witnessed unprecedented medical advances, the 5-year survival remains dismally low. Objective: This study aims to investigate the role of transmembrane protein-related genes in the development and prognosis of glioma and provide new insights into the pathogenesis of the disease. Methods: The datasets of glioma patients, including RNA sequencing data and relative clinical information, were obtained from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA) and Gene Expression Omnibus (GEO) databases. Prognostic transmembrane protein-related genes were identified by univariate Cox analysis. New disease subtypes were recognized based on the consensus clustering method, and their biological uniqueness was verified via various algorithms. The prognosis signature was constructed using the LASSO-Cox regression model, and its predictive power was validated in external datasets by receiver operating characteristic (ROC) curve analysis. An independent prognostic analysis was conducted to evaluate whether the signature could be considered a prognostic factor independent of other variables. A nomogram was constructed in conjunction with traditional clinical variables. The concordance index (C-index) and Decision Curve Analysis (DCA) were used to assess the net clinical benefit of the signature over traditional clinical variables. Seven different softwares were used to compare the differences in immune infiltration between the high- and low-risk groups to explore potential mechanisms of glioma development and prognosis. Hub genes were found using the random forest method, and their expression was based on multiple single-cell datasets. Results: Four molecular subtypes were identified, among which the C1 group had the worst prognosis. Principal Component Analysis (PCA) results and heatmaps indicated that prognosis-related transmembrane protein genes exhibited differential expression in all four groups. Besides, the microenvironment of the four groups exhibited significant heterogeneity. The 6 gene-based signatures could predict the 1-, 2-, and 3-year overall survival (OS) of glioma patients. The signature could be used as an independent prognosis factor of glioma OS and was superior to traditional clinical variables. More immune cells were infiltrated in the high-risk group, suggesting immune escape. According to our signature, many genes were associated with the content of immune cells, which revealed that transmembrane protein-related genes might influence the development and prognosis of glioma by regulating the immune microenvironment. TMEM158 was identified as the most important gene using the random forest method. The single-cell datasets consistently showed that TMEM158 was expressed in multiple malignant cells. Conclusion: The expression of transmembrane protein-related genes is closely related to the immune status and prognosis of glioma patients by regulating tumor progression in various ways. The interaction between transmembrane protein-related genes and immunity during glioma development lays the groundwork for future studies on the molecular mechanism and targeted therapy of glioma.

TMEM158 Regulates the Canonical and Non-Canonical Pathways of TGF-ß to Mediate EMT in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer with high metastatic potential. To date, no directed treatment options have been developed for the treatment of metastatic or advanced TNBC. The oncogene TMEM158, also known as RIS1, is upregulated by Ras-induced cellular senescence. Although TMEM158 has been shown to be involved in tumor progression, little is known about the molecular function and expression of TMEM158 in breast cancer. The present study evaluated the expression and prognostic relevance of TMEM158 in breast cancer patients from several databases. Gene set enrichment analysis (GSEA) showed that TMEM158 was closely associated with epithelial-mesenchymal transition (EMT) and TGF-ß pathways. Gain- and loss-of-function assays indicated that overexpressed TMEM158 might participate in EMT by activating the TGF-ß pathway, which in turn promotes tumor migration, invasion, and metastasis. These findings suggest that TMEM158 has the potential to become a new therapeutic target for TNBC.

TMEM158 expression is negatively regulated by AR signaling and associated with favorite survival outcomes in prostate cancers.

Background: Membrane protein TMEM158 was initially reported as a Ras-induced gene during senescence and has been implicated as either an oncogenic factor or tumor suppressor, depending on tumor types. It is unknown if TMEM158 expression is altered in prostate cancers. Methods: Multiple public gene expression datasets from RNA-seq and cDNA microarray assays were utilized to analyze candidate gene expression profiles. TMEM158 protein expression was assessed using an immunohistochemistry approach on a tissue section array from benign and malignant prostate tissues. Comparisons of gene expression profiles were conducted using the bioinformatics software R package. Results: COX regression-based screening identified the membrane protein TMEM158 gene as negatively associated with disease-specific and progression-free survival in prostate cancer patients. Gene expression at the mRNA and protein levels revealed that TMEM158 expression was significantly reduced in malignant tissues compared to benign compartments. Meanwhile, TMEM158 downregulation was strongly correlated with advanced clinicopathological features, including late-stage diseases, lymph node invasion, higher PSA levels, residual tumors after surgery, and adverse Gleason scores. In castration-resistant prostate cancers, TMEM158 expression was negatively correlated with AR signaling activity but positively correlated with neuroendocrinal progression index. Consistently, in cell culture models, androgen treatment reduced TMEM158 expression, while androgen deprivation led to upregulation of TMEM158 expression. Correlation analysis showed a tight correlation of TMEM158 expression with the level of R-Ras gene expression, which was also significantly downregulated in prostate cancers. Tumor immune infiltration profiling analysis discovered a strong association of TMEM158 expression with NK cell and Mast cell enrichment. Conclusion: The membrane protein TMEM158 is significantly downregulated in prostate cancer and is tightly associated with disease progression, anti-tumor immune infiltration, and patient survival outcome.

Oncogenic transmembrane protein 158 drives the PI3K/Akt signaling pathway to accelerate gastric cancer cell growth

Gastric cancer (GC) is a serious threat to human health and an important cause of cancer-related death. Herein, we evaluated the influence of transmembrane protein 158 (TMEM158) on GC cell growth. According to Genomic Spatial Event (GSE) and The Cancer Genome Atlas (TCGA) databases, TMEM158 content is amplified in GC tissues. The diagnostic value of TMEM158 expression in GC is huge. GC sufferers with high expression of TMEM158 were associated with poor overall survival. In addition, TMEM158 content was increased in GC cells. TMEM158 promoted GC cell proliferation by modulating the PI3K/Akt signaling pathway. Lack of TMEM158 reduced GC tumor growth. Collectively, TMEM158 accelerated GC cell proliferation by modulating the PI3K/Akt signaling pathway, making it a prospective biomarker for survival in GC patients.

Identification of candidate genes associated with triple negative breast cancer.

When triple negative breast cancer (TNBC) are analyzed by gene expression profiling different subclasses are identified, at least one characterized by genes related to immune signaling mechanisms supporting the role of these genes in the cancers. In an earlier study we observed differences in TNBC cell lines with respect to their expression of the cytokine IL32. Our analyses showed that certain cell lines expressed higher levels of the cytokine compared to others. Because TNBC are heterogeneous and immune-related genes appear to play a pivotal role in these cancers, we chose to examine the transcriptomes of the different cell lines based on IL32 expression. We performed group analyses of TNBC cell lines demonstrating high IL32 compared to low IL32 levels and identified IL32, GATA3, MYBL1, ETS1, PTX3 and TMEM158 as differentially associated with a subpopulation of TNBC. The six candidate genes were validated experimental and in different patient datasets. The genes distinguished a subset of TNBC from other TNBC, and TNBC from normal, luminal A, luminal B, and HER2 patient samples. The current project serves as a preliminary study in which we outline the discovery and validation of our list of six candidate genes.