Comprehensive Analysis of Alternative Splicing in Gastric Cancer Identifies Epithelial–Mesenchymal Transition Subtypes Associated with Survival

Jun, Yukyung; Suh, Yun-Suhk; Park, SungHee; Lee, Jieun; Kim, Jong‐Il; Lee, Sanghyuk; Lee, Wan‐Ping; Anczuków, Olga; Yang, Han–Kwang; Lee, Charles

doi:10.1158/0008-5472.can-21-2117

Cited by 18 publications

(17 citation statements)

References 55 publications

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“…We next analyzed expression of CD44, KRAS, and VEGF-A using RNA-sequencing data from paired tumor and adjacent normal tissue samples from 83 GA patients previously examined by Jun et al [14]. Expression of CD44, KRAS, and VEGF-A were signi cantly upregulated in tumor tissues compared with adjacent normal tissues (Fig.…”

Section: Kras Promotes Ga Spheroid Cell Secretion Of Vegf-a Fgf-2 And...mentioning

confidence: 99%

KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis

Yoon

Lü

Jun

et al. 2022

Preprint

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Our previous work showed that KRAS activation in gastric cancer cells leads to activation of an epithelial-to-mesenchymal transition (EMT) program and generation of cancer stem-like cells (CSCs). Here we analyze how this KRAS activation in gastric CSCs promotes tumor angiogenesis and metastasis. Gastric cancer CSCs were found to secrete pro-angiogenic factors such as vascular endothelial growth factor A (VEGF-A), and inhibition of KRAS markedly reduced secretion of these factors. In a genetically engineered mouse model, gastric tumorigenesis was markedly attenuated when both KRAS and VEGF-A signaling were blocked. In orthotropic implant and experimental metastasis models, silencing of KRAS and VEGF-A using shRNA in gastric CSCs abrogated primary tumor formation, lymph node metastasis, and lung metastasis far greater than individual silencing of KRAS or VEGF-A. Analysis of gastric cancer patient samples using RNA sequencing revealed a clear association between high expression of the gastric CSC marker CD44 and expression of both KRAS and VEGF-A, and high CD44 and VEGF-A expression predicted worse overall survival. In conclusion, KRAS activation in gastric CSCs enhances secretion of pro-angiogenic factors and promotes tumor progression and metastasis.

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Section: Kras Promotes Ga Spheroid Cell Secretion Of Vegf-a Fgf-2 And...mentioning

confidence: 99%

KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis

Yoon

Lü

Jun

et al. 2022

Preprint

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“…LUAD subtype classification based on AASEs showed distinct biological characteristics Molecular subtyping based on RNA splicing patterns has been shown to stratify patients with different prognosis or treatment efficacy in other tumor types, [30][31][32] , and thus could be leveraged to improve patient stratification in LUAD. Based on 3688 AASEs, we split 514 TCGA LUAD samples into three subtypes through consensus clustering analysis: G1 (n = 176, 34.2%), G2 (n = 130, 25.3%), and G3 (n = 208, 40.5%) (Supplementary Fig.…”

Section: Identification and Statistics Of Aberrant Alternative Splici...mentioning

confidence: 99%

Multi-omics analysis reveals RNA splicing alterations and their biological and clinical implications in lung adenocarcinoma

Wang

et al. 2022

Sig Transduct Target Ther

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Alternative RNA splicing is one of the most important mechanisms of posttranscriptional gene regulation, which contributes to protein diversity in eukaryotes. It is well known that RNA splicing dysregulation is a critical mechanism in tumor pathogenesis and the rationale for the promising splice-switching therapeutics for cancer treatment. Although we have a comprehensive understanding of DNA mutations, abnormal gene expression profiles, epigenomics, and proteomics in lung adenocarcinoma (LUAD), little is known about its aberrant alternative splicing profiles. Here, based on the multi-omics data generated from over 1000 samples, we systematically studied the RNA splicing alterations in LUAD and revealed their biological and clinical implications. We identified 3688 aberrant alternative splicing events (AASEs) in LUAD, most of which were alternative promoter and exon skip. The specific regulatory roles of RNA binding proteins, somatic mutations, and DNA methylations on AASEs were comprehensively interrogated. We dissected the functional implications of AASEs and concluded that AASEs mainly affected biological processes related to tumor proliferation and metastasis. We also found that one subtype of LUAD with a particular AASEs pattern was immunogenic and had a better prognosis and response rate to immunotherapy. These findings revealed novel events related to tumorigenesis and tumor immune microenvironment and laid the foundation for the development of splice-switching therapies for LUAD.

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“…Systematic profiling of splicing landscape of epithelial–mesenchymal transition (EMT) subtypes of gastric tumors indicates that RBM24 is upregulated in the tumor subtype displaying mesenchyme-specific alternative splicing, which is correlated with a poor prognosis in patients from The Cancer Genome Atlas (TCGA) clinical data [ 37 ]. In addition, the upregulation of RBM24 is positively correlated with the expression of the EMT activator ZEB1 (zinc finger E-box binding homeobox 1; previously known as TCF8), which impacts tumorigenesis by promoting migration, invasion, and metastasis [ 37 , 53 ]. This post-transcriptional activity is consistent with the function of RBM24 in alternative splicing during embryonic development [ 22 ].…”

Section: Rbm24 In Cancer Developmentmentioning

confidence: 99%

“…In this regard, it is worth mentioning that ZEB1 has been shown to play an important role in EMT and malignant progression [ 56 ]. Given the possible link between RBM24 and ZEB1 in gastric cancer [ 37 ], it will be also of interest to examine whether and how RBM24 modulates ZEB1 expression and EMT in lung cancer.…”

Section: Rbm24 In Cancer Developmentmentioning

confidence: 99%

“…Functional and correlative analyses suggest that it displays either anti-oncogenic or oncogenic potential. Several studies suggest that it suppresses tumor progression [ 28 , 29 , 30 , 31 , 32 ], while others indicate that its upregulation promotes tumor growth [ 33 , 34 , 35 , 36 , 37 ]. These raise the possibility that RBM24 may act either as a tumor suppressor or as an oncogene, functioning in a context- or background-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

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RBM24 in the Post-Transcriptional Regulation of Cancer Progression: Anti-Tumor or Pro-Tumor Activity?

Shi

2022

Cancers

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RNA-binding proteins are critical post-transcriptional regulators of gene expression. They are implicated in a wide range of physiological and pathological processes by modulating nearly every aspect of RNA metabolisms. Alterations in their expression and function disrupt tissue homeostasis and lead to the occurrence of various cancers. RBM24 is a highly conserved protein that binds to a large spectrum of target mRNAs and regulates many post-transcriptional events ranging from pre-mRNA splicing to mRNA stability, polyadenylation and translation. Studies using different animal models indicate that it plays an essential role in promoting cellular differentiation during organogenesis and tissue regeneration. Evidence is also accumulating that its dysregulation frequently occurs across human cancers. In several tissues, RBM24 clearly functions as a tumor suppressor, which is consistent with its inhibitory potential on cell proliferation. However, upregulation of RBM24 in other cancers appears to promote tumor growth. There is a possibility that RBM24 displays both anti-tumor and pro-tumor activities, which may be regulated in part through differential interactions with its protein partners and by its post-translational modifications. This makes it a potential biomarker for diagnosis and prognosis, as well as a therapeutic target for cancer treatment. The challenge remains to determine the post-transcriptional mechanisms by which RBM24 modulates gene expression and tumor progression in a context- or background-dependent manner. This review discusses recent findings on the potential function of RBM24 in tumorigenesis and provides future directions for better understanding its regulatory role in cancer cells.

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Comprehensive Analysis of Alternative Splicing in Gastric Cancer Identifies Epithelial–Mesenchymal Transition Subtypes Associated with Survival

Cited by 18 publications

References 55 publications

KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis

KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis

Multi-omics analysis reveals RNA splicing alterations and their biological and clinical implications in lung adenocarcinoma

RBM24 in the Post-Transcriptional Regulation of Cancer Progression: Anti-Tumor or Pro-Tumor Activity?

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