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 3′UTR 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 3′UTR 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.
Highlights
Cancers are biologically diverse and heterogenic and pose a major global challenge with increasing incidence, prevalence and mortality in low resource countries [1–3]
This review focuses on miRNA/alternative mRNA splicing (AS) interaction, emerging evidence shows the active involvement of the competing endogenous RNAs (ceRNAs) network in chemotherapeutic drug resistance [175,176]
Cancer drug resistance has been a challenging topic for decades in cancer biology
Summary
Cancers are biologically diverse and heterogenic and pose a major global challenge with increasing incidence, prevalence and mortality in low resource countries [1–3]. Cancer drug resistance poses a major challenge in the treatment and management of the disease This warrants urgent attention to, and targeting of, molecular alterations, such as miRNA regulation and alternative mRNA splicing, which hold potent therapeutic potential. The same type of numerous alterations in molecular mechanisms that can drive the malignant transformation of cells can drive the development of drug resistance Molecular events such as alterations in microRNA (miRNA) transcription and aberrant splicing events contribute to drug resistance in many cancers [1]. The increasing prevalence of drug resistance in cancer poses a substantial challenge in the management of the disease As a result, these molecular alterations are highly attractive drug targets to reverse the aberrant effects of miRNAs and splicing events that promote malignancy and drug resistance. MiRNA-induced cancer drug resistance; alternative mRNA splicing (AS) in cancer drug resistance; and the interplay between AS and miRNA in chemoresistance will each be discussed
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