Marima Rahaba, Francies Flavia Zita, Hull Rodney, Molefi Thulo, Oyomno Meryl, Khanyile Richard, Mbatha Sikhumbuzo, Mabongo Mzubanzi, Owen Bates David, Dlamini Zodwa
SAMRC Precision Oncology Research Unit (PORU), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfiel, Pretoria 0028, South Africa.
Department of Medical Oncology, Steve Biko Academic Hospital, University of Pretoria, Hatfield, Pretoria 0028, South Africa.
Biomedicines. 2021 Dec 2;9(12):1818. doi: 10.3390/biomedicines9121818.
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.
癌症是一种多方面的疾病，涉及多种分子机制，包括基因表达的变化。癌症中发生改变并导致基因表达变化的两个重要过程包括微小RNA（miRNA）表达的改变和异常剪接事件。miRNA是短的非编码RNA，在调节RNA沉默和基因表达中起核心作用。可变剪接通过从单个基因产生几种不同的剪接mRNA用于翻译来增加蛋白质组的多样性。miRNA表达和可变剪接事件是受到严格调控的过程。miRNA和剪接事件的失调促进包括乳腺癌、宫颈癌、前列腺癌、结直肠癌、卵巢癌和白血病在内的多种癌症的致癌作用和耐药性。可变剪接可能会改变靶mRNA的3'UTR结合位点。这种改变会影响所产生的蛋白质，并最终可能影响靶蛋白的药物亲和力，最终导致耐药性。耐药性可由内在和外在因素引起。miRNA和可变剪接之间的相互作用很大程度上是由于剪接导致miRNA的3'UTR靶向结合发生改变。这可能导致这些异构体的靶向改变以及药物靶点和耐药性的改变。此外，癌症耐药性的日益普遍给疾病的治疗带来了巨大挑战。因此，分子改变已成为极具吸引力的药物靶点，以逆转促进恶性肿瘤和耐药性的miRNA和剪接事件的异常作用。虽然癌症耐药性中miRNA-mRNA剪接的相互作用在很大程度上仍有待阐明，但本综述重点关注乳腺癌、宫颈癌、前列腺癌、结直肠癌、卵巢癌以及白血病中的miRNA和可变mRNA剪接（AS）事件，以及这些事件在耐药性中所起的作用。将讨论miRNA诱导的癌症耐药性；癌症耐药性中的可变mRNA剪接（AS）；AS和miRNA在化疗耐药性中的相互作用。尽管有这种巨大的潜力，但异常剪接事件和miRNA之间的相互作用研究不足，但在解读miRNA介导的耐药性方面具有巨大潜力。
