RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4H

Zhang, Sirui; Bao, Yufang; Shen, Xianfeng; Pan, Yunjian; Sun, Yue; Xiao, Man; Chen, Kexuan; Wei, Huanhuan; Zuo, Jiane; Saffen, David; Zong, Wei‐Xing; Sun, Yihua; Wang, Zefeng; Wang, Yongbo

doi:10.1016/j.ebiom.2020.103067

Cited by 36 publications

(45 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, our previous study showed that mutations in the gene encoding the splicing factor RNA‐binding motif protein 10 ( RBM10 ) were the hallmark of SSN tumorigenesis 29 . Another study reported that RBM10 mutations in LUAD generally lead to the loss of function and cause extensive alterations 32 . Consistent with these results, we found that the RNA splicing program was enriched in both components, suggesting that the high expression of genes related to RNA splicing contributes to tumour growth in GG and solid components.…”

Section: Discussionmentioning

confidence: 99%

Single‐cell RNA sequencing reveals the multi‐cellular ecosystem in different radiological components of pulmonary part‐solid nodules

Chen

et al. 2022

Clinical & Translational Med

View full text Add to dashboard Cite

Background Early‐stage lung adenocarcinoma that radiologically manifests as part‐solid nodules, consisting of both ground‐glass and solid components, has distinctive growth patterns and prognosis. The characteristics of the tumour microenvironment and transcriptional features of the malignant cells of different radiological phenotypes remain poorly understood. Methods Twelve treatment‐naive patients with radiological part‐solid nodules were enrolled. After frozen pathology was confirmed as lung adenocarcinoma, two regions (ground‐glass and solid) from each of the 12 part‐solid nodules and 5 normal lung tissues from 5 of the12 patients were subjected to single‐cell sequencing by 10x Genomics. We used Seurat v3.1.5 for data integration and analysis. Results We comprehensively dissected the multicellular ecosystem of the ground‐glass and solid components of part‐solid nodules at the single‐cell resolution. In tumours, these components had comparable proportions of malignant cells. However, the angiogenesis, epithelial‐to‐mesenchymal transition, KRAS, p53, and cell‐cycle signalling pathways were significantly up‐regulated in malignant cells within solid components compared to those within ground‐glass components. For the tumour microenvironment, the relative abundance of myeloid and NK cells tended to be higher in solid components than in ground‐glass components. Slight subtype composition differences existed between the ground‐glass and solid components. The T/NK cell subsets’ cytotoxic function and the macrophages’ pro‐inflammation function were suppressed in solid components. Moreover, pericytes in solid components had a stronger communication related to angiogenesis promotion with endothelial cells and tumour cells. Conclusion The cellular landscape of ground‐glass components is significantly different from that of normal tissue and similar to that of solid components. However, transcriptional differences exist in the vital signalling pathways of malignant and immune cells within these components.

show abstract

Section: Discussionmentioning

confidence: 99%

Single‐cell RNA sequencing reveals the multi‐cellular ecosystem in different radiological components of pulmonary part‐solid nodules

Chen

et al. 2022

Clinical & Translational Med

View full text Add to dashboard Cite

show abstract

“…The RNA binding motif protein 10 (RBM10) is a novel putative drug target. It is an auxiliary splicing factor that promotes exon skipping by binding to the adjacent intronic regions [ 37 ]. RBM10 was very recently found to be the second most frequently mutated gene, compared to commonly mutated tumor suppressor genes in LUAD patients.…”

Section: Lung Cancermentioning

confidence: 99%

“…RBM10 was very recently found to be the second most frequently mutated gene, compared to commonly mutated tumor suppressor genes in LUAD patients. RBM10 mutations co-occurred with major oncogenes EGFR and KRAS mutations in 93% and 78% of cases, respectively [ 37 ]. These mutations were suggested to have a role in driving LUAD development and progression, and are prevalent in female and younger non-smoking patients, highlighting RBM10 clinical significance.…”

Section: Lung Cancermentioning

confidence: 99%

See 1 more Smart Citation

Alternative RNA Splicing—The Trojan Horse of Cancer Cells in Chemotherapy

Mehterov

Kazakova

Sbirkov

et al. 2021

Genes

View full text Add to dashboard Cite

Almost all transcribed human genes undergo alternative RNA splicing, which increases the diversity of the coding and non-coding cellular landscape. The resultant gene products might have distinctly different and, in some cases, even opposite functions. Therefore, the abnormal regulation of alternative splicing plays a crucial role in malignant transformation, development, and progression, a fact supported by the distinct splicing profiles identified in both healthy and tumor cells. Drug resistance, resulting in treatment failure, still remains a major challenge for current cancer therapy. Furthermore, tumor cells often take advantage of aberrant RNA splicing to overcome the toxicity of the administered chemotherapeutic agents. Thus, deciphering the alternative RNA splicing variants in tumor cells would provide opportunities for designing novel therapeutics combating cancer more efficiently. In the present review, we provide a comprehensive outline of the recent findings in alternative splicing in the most common neoplasms, including lung, breast, prostate, head and neck, glioma, colon, and blood malignancies. Molecular mechanisms developed by cancer cells to promote oncogenesis as well as to evade anticancer drug treatment and the subsequent chemotherapy failure are also discussed. Taken together, these findings offer novel opportunities for future studies and the development of targeted therapy for cancer-specific splicing variants.

show abstract

“…RBM10 is an RNA-binding protein and a splicing regulator located on the X chromosome, which is involved in pre-mRNA (messenger RNA) splicing and post-transcriptional regulation (14). Previous studies have confirmed that RBM10 could suppress disease progression and cell proliferation in LUAD via regulating the alternative splicing of NUMB and EIF4H (15,16). Moreover, Zhao et al verified that loss-of-function mutations in RBM10 contributed to the pathogenesis of LUAD (17).…”

Section: Introductionmentioning

confidence: 99%

RBM10 Deficiency Is Associated With Increased Immune Activity in Lung Adenocarcinoma

Liu

Wang²,

Wang³

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

IntroductionRBM10 is one of the frequently mutated genes in lung adenocarcinoma (LUAD). Previous studies have confirmed that RBM10 could suppress the disease progression and cell proliferation in LUAD, but its loss-of-function mutations are more frequent in early-stage disease and decrease with the advancement of the clinical stage. This is contradictory to its role of tumor suppressor. Here, we conducted a systematic analysis to elucidate whether there was other potential biological significance of RBM10 deficiency during the progression of LUAD.Materials and MethodsThe whole exome sequencing data of 39 tumor samples from early-stage LUADs (GGN cohort) and genomic and transcriptome data of the Cancer Genome Atlas (TCGA) LUAD cohort (TCGA_LUAD cohort) and a Chinese LUAD cohort (CHOICE_ADC cohort) were first obtained. Systematic bioinformatic analyses were then conducted to determine gene expression signature, immune infiltration levels and predicted immunotherapy response. Immunohistochemistry (IHC) was also conducted to validate the result of immune infiltration.ResultsThe mutation rate of RBM10 was significantly higher in the GGN cohort than that in the TCGA_LUAD and CHOICE_ADC cohorts. In both TCGA_LUAD and CHOICE_ADC cohorts, multiple immune related pathways were markedly enriched in RBM10 deficient group. Further analyses showed that tumors with RBM10 mutations displayed higher TMB, and LUADs with RBM10 deficiency also showed higher HLA expression levels, including many HLA class I and II molecules. Additionally, many immune cells, including myeloid dendritic cells, macrophages, neutrophils and CD8+T cells, showed higher infiltration levels in LUADs with RBM10 deficiency. Finally, some immune checkpoint molecules, such as PD-L1 and TIM-3, were highly expressed in RBM10 deficient population and the predicted immunotherapy response was calculated through TIDE algorithm, showing that IFNG expression, MSI score and CD8 expression were higher in RBM10 deficient group, while MDSC and M2 macrophage were lower in RBM10 deficient group.ConclusionOur study demonstrates that RBM10 deficient LUADs show higher HLA expression and immune cell infiltration, and some immune checkpoint molecules are also highly expressed. In brief, RBM10 deficiency could enhance anti-tumor immunity in LUAD.

show abstract

RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4H

Cited by 36 publications

References 62 publications

Single‐cell RNA sequencing reveals the multi‐cellular ecosystem in different radiological components of pulmonary part‐solid nodules

Single‐cell RNA sequencing reveals the multi‐cellular ecosystem in different radiological components of pulmonary part‐solid nodules

Alternative RNA Splicing—The Trojan Horse of Cancer Cells in Chemotherapy

RBM10 Deficiency Is Associated With Increased Immune Activity in Lung Adenocarcinoma

Contact Info

Product

Resources

About