Increased cell apoptosis in human lung adenocarcinoma and in vivo tumor growth inhibition by RBM10, a tumor suppressor gene

Ji, Yunxi; Xie, Sheng; Jiang, Li; Liu, Lijian; Li, Liumei; Luo, Lichuan; Yan, Chen; Zhang, Jianxuan; Yu, Lei; Zhang, Yao-Zhong; Tang, Nong; Liu, Bugu

doi:10.3892/ol.2017.6765

Cited by 15 publications

(15 citation statements)

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“…The analyses of LUAD samples in TCGA indicate that RBM10 mutations may contribute to LUAD progression [32] and associate with a number of splicing changes [33] . Previous functional studies using lung cancer cell lines showed contradictory roles of RBM10 in LUAD progression [34] , [35] , [36] , [37] . Therefore, the exact function and underlying molecular mechanism of RBM10 in lung cancer remain to be determined.…”

Section: Introductionmentioning

confidence: 95%

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

et al. 2020

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Background RNA splicing defects are emerging molecular hallmarks of cancer. The gene encoding splicing factor RNA binding motif protein 10 (RBM10) has been found frequently mutated in various types of cancer, particularly lung adenocarcinoma (LUAD), but how RBM10 affects cancer pathogenesis remains to be determined. Moreover, the functional roles and clinical significance of RBM10 mutation-associated splicing events in LUAD are largely unknown. Methods RBM10 mutations and their functional impacts were examined in LUAD patients from a Chinese patient cohort and The Cancer Genome Atlas (TCGA). Alternative splicing (AS) changes induced by RBM10 mutations in LUAD were identified by RNA sequencing and correlated with patient survival. Functions of RBM10 and the splice variants of eukaryotic translation initiation factor 4H containing or lacking exon 5 ( EIF4H-L and EIF4H-S respectively) in LUAD development and progression were examined by cellular phenotypic assays and xenograft tumour formation. Findings RBM10 mutations in LUAD generally lead to loss-of-function and cause extensive alterations in splicing events that can serve as prognostic predictors. RBM10 suppresses LUADprogression largely by regulating alternative splicing of EIF4H exon 5. Loss of RBM10 in LUAD enhances the expression of EIF4H-L in LUAD. EIF4H-L , but not EIF4H-S , is critical for LUAD cell proliferation, survival and tumourigenesis. Interpretation Our study demonstrates a new molecular mechanism underlying RBM10 suppressive functions in lung cancer and the therapeutic value of RBM10-regulated AS events, providing important mechanistic and translational insights into splicing defects in cancer.

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Section: Introductionmentioning

confidence: 95%

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

et al. 2020

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“…RBM10, a tumor suppressor gene [28,29], encodes a nuclear protein that contains an RNArecognition motif. RBM10 regulates pre-mRNA splicing in the alternative splicing pathway [30].…”

Section: Discussionmentioning

confidence: 99%

Mutation profile of non-small cell lung cancer revealed by next generation sequencing

Chang

Chen

et al. 2020

Preprint

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Background: Precision therapy for lung cancer requires comprehensive genomic analyses. Specific effects of targeted therapies have been reported in Asia populations, including Taiwanese, but genomic studies have rarely been performed in these populations. Method: We enrolled 72 patients with non-small cell lung cancer, of whom 61 had adenocarcinoma, 10 had squamous cell carcinoma, and 1 had combined adenocarcinoma and squamous cell carcinoma. Whole-exome or targeted gene sequencing was performed. To identify trunk mutations, we performed whole-exome sequencing in two tumor regions in four patients.Results: Nineteen known driver mutations in EGFR, PIK3CA, KRAS, CTNNB1, and MET were identified in 34 of the 72 tumors evaluated (47.22%). A comparison with the Cancer Genome Atlas dataset showed that EGFR was mutated at a much higher frequency in our cohort than in Caucasians, whereas KRAS and TP53 mutations were found in only 5.56% and 25% of our Taiwanese patients, respectively. We also identified new mutations in ARID1A, ARID2, CDK12, CHEK2, GNAS, H3F3A, KDM6A, KMT2C, NOTCH1, RB1, RBM10, RUNX1, SETD2, SF3B1, SMARCA4, THRAP3, TP53, and ZMYM2. Moreover, all ClinVar pathogenic variants were trunk mutations present in two regions of a tumor. RNA sequencing revealed that the trunk or branch genes were expressed at similar levels among different tumor regions.Conclusions: We identified novel variants potentially associated with lung cancer tumorigenesis. The specific mutation pattern in Taiwanese patients with non-small cell lung cancer may influence targeted therapies.

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“…RBM10, a tumor suppressor gene [28,29], encodes a nuclear protein that contains an RNA-recognition motif. RBM10 regulates pre-mRNA splicing in the alternative splicing pathway [30].…”

Section: Discussionmentioning

confidence: 99%

Mutation profile of non-small cell lung cancer revealed by next generation sequencing

Chang

Chen

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Precision therapy for lung cancer requires comprehensive genomic analyses. Specific effects of targeted therapies have been reported in Asia populations, including Taiwanese, but genomic studies have rarely been performed in these populations. Method: We enrolled 72 patients with non-small cell lung cancer, of whom 61 had adenocarcinoma, 10 had squamous cell carcinoma, and 1 had combined adenocarcinoma and squamous cell carcinoma. Whole-exome or targeted gene sequencing was performed. To identify trunk mutations, we performed whole-exome sequencing in two tumor regions in four patients. Results: Nineteen known driver mutations in EGFR, PIK3CA, KRAS, CTNNB1, and MET were identified in 34 of the 72 tumors evaluated (47.22%). A comparison with the Cancer Genome Atlas dataset showed that EGFR was mutated at a much higher frequency in our cohort than in Caucasians, whereas KRAS and TP53 mutations were found in only 5.56% and 25% of our Taiwanese patients, respectively. We also identified new mutations in ARID1A, ARID2, CDK12, CHEK2, GNAS, H3F3A, KDM6A, KMT2C, NOTCH1, RB1, RBM10, RUNX1, SETD2, SF3B1, SMARCA4, THRAP3, TP53, and ZMYM2. Moreover, all ClinVar pathogenic variants were trunk mutations present in two regions of a tumor. RNA sequencing revealed that the trunk or branch genes were expressed at similar levels among different tumor regions.Conclusions: We identified novel variants potentially associated with lung cancer tumorigenesis. The specific mutation pattern in Taiwanese patients with non-small cell lung cancer may influence targeted therapies.

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Increased cell apoptosis in human lung adenocarcinoma and in vivo tumor growth inhibition by RBM10, a tumor suppressor gene

Cited by 15 publications

References 35 publications

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

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

Mutation profile of non-small cell lung cancer revealed by next generation sequencing

Mutation profile of non-small cell lung cancer revealed by next generation sequencing

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