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.

The VEGF/VEGFR Axis Revisited: Implications for Cancer Therapy

“…Alternative splicing involves the removal of introns from pre-messenger ribonucleic acid (pre-mRNA), with the remaining exons being connected to each other in different combinations to form mRNAs [ 32 , 33 ]. When dysregulated, the generation of variants that promote tumorigenesis may occur [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Moreover, some of the variants formed from the alternative splicing of full-length or total VEGF are linked to impaired angiogenesis and tumor progression [ 35 , 36 ].…”

“…When dysregulated, the generation of variants that promote tumorigenesis may occur [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Moreover, some of the variants formed from the alternative splicing of full-length or total VEGF are linked to impaired angiogenesis and tumor progression [ 35 , 36 ]. The discovery of several VEGF isoforms with distinct functions has revealed that the physiology of VEGF is more complex than previously thought [ 37 ].…”

MicroRNA and Alternative mRNA Splicing Events in Cancer Drug Response/Resistance: Potent Therapeutic Targets

“…Tumors resistant to this are known as castration resistant PCa (CRPC) and are treated with androgen receptor (AR) blockers, such as Enzalutamide (Enza). Alternative splicing of the androgen receptor has been observed in CRPC [ 101 ]. An analysis of splicing events in drug resistant prostate cancer revealed alternative splicing events in RNA binding proteins that are under control of the Myc signaling pathway.…”

Cohesin regulates alternative splicing

“…Among the diseases where cohesin mutations have been found is acute myeloid leukemia (AML), where mutations in cohesin components occur at a frequency of up to 20% (10)(11)(12). AML is frequently associated with large changes in patterns of alternative splicing, where it has been estimated that more than 2000 transcripts undergo altered splicing, with distinct patterns associated with chemosensitivity or resistance (13). Splicing in mammalian systems is mediated by the spliceosome, a multi-megadalton complex that assembles on intronic 5′ and 3′ splice sites (14).…”