RNA splicing and splicing regulator changes in prostate cancer pathology

Munkley, Jennifer; Livermore, Karen E.; Rajan, Prabhakar; Elliott, David

doi:10.1007/s00439-017-1792-9

Cited by 55 publications

(63 citation statements)

References 76 publications

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“…However, tumor cells are capable of producing abnormal proteins with altered, missing, or inserted domains, resulting in carcinogenesis . Recent studies have confirmed the close relationship between abnormal AS and oncogenic processes, including therapeutic resistance, tumor progression, and metastasis . Moreover, altered expression or mutations of splicing factors can result in global alterations in AS behavior, leading to oncogene and cancer pathway activation, and production of other cancer‐promoting splicing isoforms .…”

Section: Introductionmentioning

confidence: 99%

“…4 Recent studies have confirmed the close relationship between abnormal AS and oncogenic processes, including therapeutic resistance, tumor progression, and metastasis. [4][5][6][7] Moreover, altered expression or mutations of splicing factors can result in global alterations in AS behavior, leading to oncogene and cancer pathway activation, and production of other cancer-promoting splicing isoforms. [8][9][10][11] These findings suggest that tumor-specific splice variants might be effective diagnostic, predictive, and prognostic biomarkers, and may also be promising therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

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Profiles of prognostic alternative splicing signature in hepatocellular carcinoma

Chen

Liu

et al. 2020

Cancer Medicine

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Previous studies have demonstrated the role of abnormal alternative splicing (AS) in tumor progression. This study examines the prognostic index (PI) of alternative splices (ASs) in patients with hepatocellular carcinoma (HCC). The clinical features and splicing events of patients with HCC were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed AS (DEAS) were compared between HCC and adjacent normal samples. Univariate Cox regression analysis was used to determine changes in DEAS associated with overall survival (OS). A PI was generated from OS‐associated DEASs using Kaplan‐Meier curves, receiver operating characteristic (ROC) curves, multivariate Cox regression, and cluster analysis. Then, the correlation between DEASs and splicing factors was assessed, followed by functional and pathway enrichment analysis. We identified 34 163 ASs of 8985 genes in HCC, and 153 OS‐ASs were identified using univariate Cox regression analysis. Low‐ and high‐PI groups were determined based on the median “PI‐ALL” value according to significantly different survival (P = 2.2e − 16). The ROC curve of all PI (PI‐ALL) had an area under the curve (AUC) of 0.993 for survival status in patients with HCC. A potential regulatory network associated with prognosis of patients with HCC was established. Enrichment analysis also resulted in the identification of several pathways potentially associated with carcinogenesis and progression of HCC. Four clusters were identified that were associated with clinical features and prognosis. Our study generated comprehensive profiles of ASs in HCC. The interaction network and functional connections were used to elucidate the underlying mechanisms of AS in HCC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Profiles of prognostic alternative splicing signature in hepatocellular carcinoma

Chen

Liu

et al. 2020

Cancer Medicine

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“…31 Independent of DNA-level genetic mutations and alterations, alternative splicing represents another process by which a single gene can produce various Cancer February 15, 2020 mRNA and protein isoforms with related, distinct, or even opposing functional differences that can have profound biological consequences. 12,32,33 Using microarray analysis, we confirmed several tumor-specific splice variants of the LAMA3, DST, and TP63 genes in HNSCC, 34 and used RNA sequencing analysis to identify the oncogenic splice variant of AKT3 and DOCK5 in HPV-positive HNSCC and HPV-negative HNSCC, respectively. Alternative RNA splicing is one of the main cellular engines that expands the complexity and diversity of the eukaryotic proteome.…”

Section: Discussionmentioning

confidence: 81%

“…9 The genome-wide mapping of alternative splicing variants also has been identified in a variety of tumors, including gastric, prostate, and breast cancer as well as other tumors. 12,32,33 Using microarray analysis, we confirmed several tumor-specific splice variants of the LAMA3, DST, and TP63 genes in HNSCC, 34 and used RNA sequencing analysis to identify the oncogenic splice variant of AKT3 and DOCK5 in HPV-positive HNSCC and HPV-negative HNSCC, respectively. 15,16 In addition to a specific DOCK5 variant, a total of 580 ASEs associated with HPV-negative HNSCC were determined using outlier analysis, including the specific LOXL2 variant with a novel inserted exon.…”

Section: Discussionmentioning

confidence: 81%

A novel splice variant of LOXL2 promotes progression of human papillomavirus–negative head and neck squamous cell carcinoma

Liu

Guo

Sakai

et al. 2019

Cancer

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BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently diagnosed cancers worldwide. LOXlike (LOXL) 2 (LOXL2) demonstrates alternative splicing events in patients with human papillomavirus (HPV)-negative HNSCC. The current study explored the role of a dominant LOXL2 variant in HPV-negative HNSCC. METHODS: Expression of the LOXL2 variant was analyzed using The Cancer Genome Atlas cohorts and validated using quantitative reverse transcriptase-polymerase chain reaction in a separate primary tumor set. The authors defined the effect of LOXL2 splice variants in assays for cell proliferation using a cell viability assay and colony formation assay. Cell migration and invasion were examined using a cell scratch assay and transwell cell migration and invasion assay in LOXL2 splice variant gain and loss of expression cells. Western blot analysis and gene set enrichment analysis were used to explore the potential mechanism of the LOXL2 splice variant in HPV-negative HNSCC. RESULTS: Expression of a novel LOXL2 variant was found to be upregulated in The Cancer Genome Atlas HPV-negative HNSCC, and confirmed in the separate primary tumor validation set. Analyses of loss and gain of function demonstrated that this LOXL2 variant enhanced proliferation, migration, and invasion in HPV-negative HNSCC cells and activated the FAK/AKT pathway. A total of 837 upregulated and 820 downregulated genes and 526 upregulated and 124 downregulated pathways associated with LOXL2 variant expression were identified using gene set enrichment analysis, which helped in developing a better understanding of the networks activated by this LOXL2 variant in patients with HPV-negative HNSCC. CONCLUSIONS: The novel LOXL2 variant can promote the progression of HPV-negative HNSCC, in part through FAK/AKT pathway activation, which may provide a new potential therapeutic target among patients with HPV-negative HNSCC. Cancer 2020;126:737-748.

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“…It is still unclear whether drug toxicity can influence the phenotypes of mRNA isoforms, or whether drug-induced changes in mRNA isoform patterns is a key molecular mechanism by which drugs can interrupt gene function by switching mRNA isoform production. The androgen regulates a number of related genes to induce spliced mRNA isoforms, including a prostate-specific splice isoform of ST6GALNAC1 mRNA (Munkley et al 2017). Genetic rearrangements often occur in the early stages of diseases, leading to different patterns of alternative splicing and RNA isoforms in response to drug and to abnormal protein expression, synthesis, and activation.…”

mentioning

confidence: 99%