Alternative RNA Splicing-The Trojan Horse of Cancer Cells in Chemotherapy

Abstract

Almost all transcribed human genes undergo alternative RNA splicing, which increases the diversity of the coding and non-coding cellular landscape. The resultant gene products might have distinctly different and, in some cases, even opposite functions. Therefore, the abnormal regulation of alternative splicing plays a crucial role in malignant transformation, development, and progression, a fact supported by the distinct splicing profiles identified in both healthy and tumor cells. Drug resistance, resulting in treatment failure, still remains a major challenge for current cancer therapy. Furthermore, tumor cells often take advantage of aberrant RNA splicing to overcome the toxicity of the administered chemotherapeutic agents. Thus, deciphering the alternative RNA splicing variants in tumor cells would provide opportunities for designing novel therapeutics combating cancer more efficiently. In the present review, we provide a comprehensive outline of the recent findings in alternative splicing in the most common neoplasms, including lung, breast, prostate, head and neck, glioma, colon, and blood malignancies. Molecular mechanisms developed by cancer cells to promote oncogenesis as well as to evade anticancer drug treatment and the subsequent chemotherapy failure are also discussed. Taken together, these findings offer novel opportunities for future studies and the development of targeted therapy for cancer-specific splicing variants.

Keywords: alternative splicing; cancer pathobiology; drug resistance; splice variants.

Figure 1

Different types of AS events. Constitutive splicing, exon skipping, alternative 5′ and 3′ sites, mutually exclusive exons, and intron retention are shown. The pre-mRNAs are shown above the arrows; the mature mRNA variants following AS are shown below the arrows.

Figure 2

Examples of AS events leading to cancer drug resistance. The AS of HER2, ECT2, EZH2, and VEGFA conferring resistance or sensitivity, respectively, to Trastuzumab, Doxorubicin, Enzalutamide, and Bevacizumab is shown.

Figure 3

Cancer-related genes undergoing AS and their significance for drug resistance. The figure summarizes representative AS events that contribute to chemotherapy failure in different cancers. PRMT5 (Protein Arginine Methyltransferase 5); FGFR1 (Fibroblast Growth Factor Receptor 1); SRSF3 (Serine and Arginine Rich Splicing Factor 3); ErbB2 (Erb-B2 Receptor Tyrosine Kinase 2); EIF4H (Eukaryotic Translation Initiation Factor 4H); VEGFA (Vascular Endothelial Growth Factor A); TIA-1 (TIA1 Cytotoxic Granule Associated RNA Binding Protein); AR (Androgen Receptor); GR (Glucocorticoid receptor); P53 (Tumor Protein P53); Bcl-x (BCL2 Apoptosis Regulator).