Abstract:
Cancer is a multifaceted disease that involves several molecular mechanisms including
changes in gene expression. Two important processes altered in cancer that lead to changes in gene
expression include altered microRNA (miRNA) expression and aberrant splicing events. MiRNAs
are short non-coding RNAs that play a central role in regulating RNA silencing and gene expression.
Alternative splicing increases the diversity of the proteome by producing several different spliced
mRNAs from a single gene for translation. MiRNA expression and alternative splicing events are
rigorously regulated processes. Dysregulation of miRNA and splicing events promote carcinogenesis
and drug resistance in cancers including breast, cervical, prostate, colorectal, ovarian and leukemia.
Alternative splicing may change the target mRNA 30UTR binding site. This alteration can affect
the produced protein and may ultimately affect the drug affinity of target proteins, eventually
leading to drug resistance. Drug resistance can be caused by intrinsic and extrinsic factors. The
interplay between miRNA and alternative splicing is largely due to splicing resulting in altered
30UTR targeted binding of miRNAs. This can result in the altered targeting of these isoforms and
altered drug targets and drug resistance. Furthermore, the increasing prevalence of cancer drug
resistance poses a substantial challenge in the management of the disease. Henceforth, molecular
alterations have become highly attractive drug targets to reverse the aberrant effects of miRNAs and
splicing events that promote malignancy and drug resistance. While the miRNA–mRNA splicing
interplay in cancer drug resistance remains largely to be elucidated, this review focuses on miRNA
and alternative mRNA splicing (AS) events in breast, cervical, prostate, colorectal and ovarian
cancer, as well as leukemia, and the role these events play in drug resistance. MiRNA induced
cancer drug resistance; alternative mRNA splicing (AS) in cancer drug resistance; the interplay
between AS and miRNA in chemoresistance will be discussed. Despite this great potential, the interplay between aberrant splicing events and miRNA is understudied but holds great potential in
deciphering miRNA-mediated drug resistance.
