Alternative splicing of mRNA in colorectal cancer: new strategies for tumor diagnosis and treatment

Chen, Yanyan; Huang, Mengxi; Liu, Xiaolong; Huang, Yunbo; Liu, Chao; Zhu, Jialong; Fu, Gongbo; Lei, Zengjie; Chen, Xiaoyuan

doi:10.1038/s41419-021-04031-w

Cited by 17 publications

(11 citation statements)

References 138 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Altered splicing machinery has been linked to cancer [ 12 ]. More than 90% of genes are alternatively spliced, and disturbances to this complex machinery could result in the initiation and progression of cancer [ 13 , 14 ] Molecular changes in splicing genes and altered ratios of abundance of splice variants have been associated with the occurrence, increased progression and adverse prognosis of many types of cancer, including colorectal, breast, prostate and blood cancer [ 15 , 16 , 17 , 18 ]). Therefore, studying the alternative splicing (AS) events happening in CRC would allow for the identification of biomarkers that could be used for predictive diagnosis, prognosis, patient stratification and treatment selection.…”

Section: Introductionmentioning

confidence: 99%

Alternatively Spliced Isoforms of MUC4 and ADAM12 as Biomarkers for Colorectal Cancer Metastasis

Althenayyan

AlMuhanna

AlAbdulrahman

et al. 2023

JPM

View full text Add to dashboard Cite

There is a pertinent need to develop prognostic biomarkers for practicing predictive, preventive and personalized medicine (PPPM) in colorectal cancer metastasis. The analysis of isoform expression data governed by alternative splicing provides a high-resolution picture of mRNAs in a defined condition. This information would not be available by studying gene expression changes alone. Hence, we utilized our prior data from an exon microarray and found ADAM12 and MUC4 to be strong biomarker candidates based on their alternative splicing scores and pattern. In this study, we characterized their isoform expression in a cell line model of metastatic colorectal cancer (SW480 & SW620). These two genes were found to be good prognostic indicators in two cohorts from The Cancer Genome Atlas database. We studied their exon structure using sequence information in the NCBI and ENSEMBL genome databases to amplify and validate six isoforms each for the ADAM12 and MUC4 genes. The differential expression of these isoforms was observed between normal, primary and metastatic colorectal cancer cell lines. RNA-Seq analysis further proved the differential expression of the gene isoforms. The isoforms of MUC4 and ADAM12 were found to change expression levels in response to 5-Fluorouracil (5-FU) treatment in a dose-, time- and cell line-dependent manner. Furthermore, we successfully detected the protein isoforms of ADAM12 and MUC4 in cell lysates, reflecting the differential expression at the protein level. The change in the mRNA and protein expression of MUC4 and ADAM12 in primary and metastatic cells and in response to 5-FU qualifies them to be studied as potential biomarkers. This comprehensive study underscores the importance of studying alternatively spliced isoforms and their potential use as prognostic and/or predictive biomarkers in the PPPM approach towards cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

Alternatively Spliced Isoforms of MUC4 and ADAM12 as Biomarkers for Colorectal Cancer Metastasis

Althenayyan

AlMuhanna

AlAbdulrahman

et al. 2023

JPM

View full text Add to dashboard Cite

show abstract

“…Another example of gene-specific AS alteration is represented by the DNA mismatch repair hMlh1 (MutL Homolog 1) gene. Several aberrant, shorter transcripts (such as delEx6–9, delEx9–10, delEx10, delEx11, delEx10–11, delEx16, and delEx17) of the hMlh1 gene were observed in colon cancer and gastric cancer patients and cell lines and in a Lynch syndrome cohort [ 66 , 67 , 68 , 69 ], but their specific functional activities have not yet been clarified. The expression of deleted hMlh1 transcripts has been described also in patients with acute lymphoblastic leukaemia (ALL), with the delEx9–10 splice variant having a dominant negative effect on the mismatch repair function of the wild type protein [ 70 ].…”

Section: Histone Ptms and Altered Splicing Events In Cancermentioning

confidence: 99%

Histone Marks-Dependent Effect on Alternative Splicing: New Perspectives for Targeted Splicing Modulation in Cancer?

Imbriano

Belluti

2022

IJMS

View full text Add to dashboard Cite

Alternative splicing (AS) is a tightly regulated mechanism that generates the complex human proteome from a small number of genes. Cis-regulatory RNA motifs in exons and introns control AS, recruiting positive and negative trans-acting splicing regulators. At a higher level, chromatin affects splicing events. Growing evidence indicates that the popular histone code hypothesis can be extended to RNA-level processes, such as AS. In addition to nucleosome positioning, which can generate transcriptional barriers to shape the final splicing outcome, histone post-translational modifications can contribute to the detailed regulation of single exon inclusion/exclusion. A histone-based system can identify alternatively spliced chromatin stretches, affecting RNAPII elongation locally or recruiting splicing components via adaptor complexes. In tumor cells, several mechanisms trigger misregulated AS events and produce cancer-associated transcripts. On a genome-wide level, aberrant AS can be the consequence of dysfunctional epigenetic splicing code, including altered enrichment in histone post-translational modifications. This review describes the main findings related to the effect of histone modifications and variants on splicing outcome and how a dysfunctional epigenetic splicing code triggers aberrant AS in cancer. In addition, it highlights recent advances in programmable DNA-targeting technologies and their possible application for AS targeted epigenetic modulation.

show abstract

“…Cancer-specific splice variants may potentially be used as diagnostic, prognostic, and predictive biomarkers of various tumors. Moreover, the specificity of these isoforms to cancer cells compared with normal cells makes CaD an ideal selective therapeutic target in cancers[ 94 ].…”

Section: L-cad Is a Tumor-specific Splice Variantmentioning

confidence: 99%

Emerging role of caldesmon in cancer: A potential biomarker for colorectal cancer and other cancers

Alnuaimi¹,

Nair²,

Malhab³

et al. 2022

WJGO

View full text Add to dashboard Cite

Colorectal cancer (CRC) is a devastating disease, mainly because of metastasis. As a result, there is a need to better understand the molecular basis of invasion and metastasis and to identify new biomarkers and therapeutic targets to aid in managing these tumors. The actin cytoskeleton and actin-binding proteins are known to play an important role in the process of cancer metastasis because they control and execute essential steps in cell motility and contractility as well as cell division. Caldesmon (CaD) is an actin-binding protein encoded by the CALD1 gene as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight CaD, expressed in smooth muscle, and low-molecular weight CaD (l-CaD), expressed in nonsmooth muscle cells. According to our comprehensive review of the literature, CaD, particularly l-CaD, plays a key role in the development, metastasis, and resistance to chemoradiotherapy in colorectal, breast, and urinary bladder cancers and gliomas, among other malignancies. CaD is involved in many aspects of the carcinogenic hallmarks, including epithelial mesenchymal transition via transforming growth factor-beta signaling, angiogenesis, resistance to hormonal therapy, and immune evasion. Recent data show that CaD is expressed in tumor cells as well as in stromal cells, such as cancer-associated fibroblasts, where it modulates the tumor microenvironment to favor the tumor. Interestingly, CaD undergoes selective tumor-specific splicing, and the resulting isoforms are generally not expressed in normal tissues, making these transcripts ideal targets for drug design. In this review, we will analyze these features of CaD with a focus on CRC and show how the currently available data qualify CaD as a potential candidate for targeted therapy in addition to its role in the diagnosis and prognosis of cancer.

show abstract

Alternative splicing of mRNA in colorectal cancer: new strategies for tumor diagnosis and treatment

Cited by 17 publications

References 138 publications

Alternatively Spliced Isoforms of MUC4 and ADAM12 as Biomarkers for Colorectal Cancer Metastasis

Alternatively Spliced Isoforms of MUC4 and ADAM12 as Biomarkers for Colorectal Cancer Metastasis

Histone Marks-Dependent Effect on Alternative Splicing: New Perspectives for Targeted Splicing Modulation in Cancer?

Emerging role of caldesmon in cancer: A potential biomarker for colorectal cancer and other cancers

Contact Info

Product

Resources

About