Alternative splicing events implicated in carcinogenesis and prognosis of colorectal cancer

Liu, Jingwei; Li, Hao; Shen, Shixuan; Sun, Liping; Yuan, Yuan; Xing, Chengzhong

doi:10.7150/jca.24569

Cited by 61 publications

(51 citation statements)

References 32 publications

(28 reference statements)

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“…Moreover, CALD1 encodes the caldesmon protein, which is a calmodulin-binding and cytoskeleton-associated protein and regulates cell motility, such as migration and invasion (40,41). It has been suggested that CALD1 may indicate a general splicing event associated with cancer (41,42) and was also identified as a potential prognostic molecular marker for bladder and colon cancer (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer

Zhang

et al. 2020

Oncol Rep

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Establishing a prognostic genetic signature closely related to the tumor immune microenvironment (TIME) to predict clinical outcomes is necessary. Using the Gene Expression Omnibus (GEO) database of a non-small cell lung cancer (NSCLC) cohort and the immune score derived from the Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm, we applied the least absolute shrinkage and selection operator (LASSO) Cox regression model to screen a 10-gene signature among the 448 differentially expressed genes and found that the risk prediction models constructed by 10 genes could be more sensitive to prognosis than TNM (Tumor, Lymph node and Metastasis) stage (P=0.006). The CIBERSORT method was applied to quantify the relative levels of different immune cell types. It was found that the ratio of eosinophils, mast cells (MCs) resting and CD4 T cells memory activated in the low-risk group was higher than that in the high-risk group, and the difference was statistically significant (P= 0.003, P= 0.014 and P= 0.018, respectively). Inconsistently, the ratio of resting natural killer (NK) cells and activated plasma cells in the low-risk group was significantly lower than that in the high-risk group (P= 0.05 and P=0.009, respectively). Kaplan-Meier survival results showed that patients of the high-risk group had significantly shorter overall survival (OS) than those of the low-risk group in the training set (P<0.001). Furthermore, Kaplan-Meier survival showed that patients of the high-risk group had significantly shorter OS than those of the low-risk group (P=0.0025 and P=0.0157, respectively) in the validation set [GSE31210 and TCGA (The Cancer Genome Atlas)]. The 10-gene signature was found to be an independent risk factor for prognosis in univariate and multivariate Cox proportional hazard regression analyses (P<0.001). In addition, it was found that the risk model constructed by the 10-gene signature was related to the clinical related factors in logistic regression analysis. The genetic signature closely related to the immune microenvironment was found to be able to predict differences in the proportion of immune cells (eosinophils, resting MCs, memory activated CD4 T cells, resting NK cells and plasma cells) in the risk model. Our findings suggest that the genetic signature closely related to TIME could predict the prognosis of NSCLC patients, and provide some reference for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer

Zhang

et al. 2020

Oncol Rep

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“…Alternative splicing is a common phenomenon in mammalian cells that is tightly associated with the post-splicing steps of mRNA transcription, as well as the synthesis of various protein isoforms [19,20]. Abnormal patterns of prem-RNA alternative splicing are prevalent in human malignancies [21,22], yet the molecular mechanisms of these alterations remain poorly defined. The SR proteins are splicing regulators, characterized by a unique domain enriched with serine/arginine repeats, which have essential roles in premRNA alternative splicing and gene expression [23,24].…”

Section: Discussionmentioning

confidence: 99%

Cooperation of SRPK2, Numb and p53 in the malignant biology and chemosensitivity of colorectal cancer

et al. 2020

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Serine-arginine protein kinase 2 (SRPK2) is aberrantly expressed in human malignancies including colorectal cancer (CRC). However, little is known about the molecular mechanisms, and the role of SRPK2 in chemosensitivity remains unexplored in CRC. We recently showed that SRPK2 promotes pancreatic cancer progression by down-regulating Numb and p53. Therefore, we investigated the cooperation between SRPK2, Numb and p53 in the cell migration, invasion and chemosensitivity of CRC in vitro. Here, we showed that SRPK2 expression was higher in CRC tumors than in nontumor tissues. SRPK2 expression was positively associated with clinicopathological characteristics of CRC patients, including tumor differentiation, T stage, N stage and UICC stage. Additionally, SRPK2 had no association with mutant p53 (mtp53) in SW480 and SW620 cells, but negatively regulated Numb and wild-type p53 (wtp53) in response to 5-fluorouracil or cisplatin treatment in HCT116 cells. Moreover, SRPK2, Numb and p53 coimmunoprecipitated into a triple complex with or without the treatment of 5-fluorouracil in HCT116 cells, and p53 knockdown reversed the up-regulation of wtp53 induced by SRPK2 silencing with chemical agent treatment. Furthermore, overexpression of SRPK2 increased cell migration and invasion and decreased chemosensitivity to 5-fluorouracil or cisplatin in HCT116 cells. Conversely, SRPK2 silencing decreased cell migration and invasion and increased chemosensitivity to 5-fluorouracil or cisplatin, yet these effects could be reversed by p53 knockdown under chemical agent treatment. These results thus reveal a novel role of SRPK2-Numb-p53 signaling in the progression of CRC and demonstrate that SRPK2 is a potential therapeutic target for CRC clinical therapy.

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“…Global splicing changes in cancer have been studied using microarray or RNA-seq techniques in the past [11][12][13]. Compared to microarray (eg.…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant splicing events in CRC and/or other cancer types were identified using either microarray or RNA-seq techniques in the past [11][12][13]. The roles of alternative splicing in CRC were reported for individual genes: ITGA6 [14], MAP4K4 [15], EPDR1, ZNF518B [16], FIR [17], BRAF [18], Rac1 [19], OCT4 [20], RON [21], CD44 [22,23].…”

Section: Introductionmentioning

confidence: 99%

Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer

Jia¹,

Wang

Lian

et al. 2019

Preprint

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Alternative splicing is an important mechanism of regulating eukaryotic gene expression. Understanding the most common alternative splicing events in colorectal cancer (CRC) will help developing diagnostic, prognostic or therapeutic tools in CRC. Publicly available RNA-seq data of 31 pairs of CRC and normal tissues and 18 pairs of metastatic and normal tissues were used to identify alternative splicing events using PSI and DEXSeq methods. The highly significant splicing events were used to search a database of The Cancer Genome Atlas (TCGA). We identified alternative splicing events in 10 genes marking the signature of CRC (more inclusion of CLK1-E4, COL6A3-E6, CD44v8-10, alternative first exon regulation of ARHGEF9, CHEK1, HKDC1 and HNF4A) or metastasis (decrease of SERPINA1-E1a, CALD-E5b, E6 and FBLN2-E9). Except for CHEK1, all other 9 splicing events were confirmed by TCGA data with 382 CRC tumors and 52 normal controls. Two splicing events (COL6A3 and HKDC1) were found to be significantly associated with patient overall survival. The alternative splicing signatures of the 10 genes are highly consistent with previous reports and/or relevant to cancer biology. The significant association of higher expression of the COL6A3 E5-E6 junction and HKDC1 E1-E2 with better overall survival was firstly reported. This study might be of significant value in the future biomarker, prognosis marker and therapeutics development of CRC.

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Alternative splicing events implicated in carcinogenesis and prognosis of colorectal cancer

Cited by 61 publications

References 32 publications

A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer

A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer

Cooperation of SRPK2, Numb and p53 in the malignant biology and chemosensitivity of colorectal cancer

Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer

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