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

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.

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Molecular Imaging of Gene Expression and Protein Function In Vivo: Cancer Drug Targets and Drug Resistance

Toxicologic Pathology ◽

10.1080/714592180 ◽

2004 ◽

Vol 32 (1) ◽

pp. 153-153

Keyword(s):

Gene Expression ◽

Drug Resistance ◽

Molecular Imaging ◽

Protein Function ◽

Drug Targets ◽

Cancer Drug

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Utilization of optically induced dielectrophoresis in a microfluidic system for sorting and isolation of cells with varied degree of viability: Demonstration of the sorting and isolation of drug-treated cancer cells with various degrees of anti-cancer drug resistance gene expression

Sensors and Actuators B Chemical ◽

10.1016/j.snb.2018.12.047 ◽

2019 ◽

Vol 283 ◽

pp. 621-631 ◽

Cited By ~ 9

Author(s):

Po-Yu Chu ◽

Chia-Jung Liao ◽

Chia-Hsun Hsieh ◽

Hung-Ming Wang ◽

Wen-Pin Chou ◽

...

Keyword(s):

Gene Expression ◽

Drug Resistance ◽

Cancer Cells ◽

Resistance Gene ◽

Microfluidic System ◽

Cancer Drug ◽

Drug Resistance Gene ◽

Cancer Drug Resistance ◽

Anti Cancer ◽

Varied Degree

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Abstract 15: Global RNA Splicing Regulation in Cardiac Maturation

Circulation Research ◽

10.1161/res.117.suppl_1.15 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Chen Gao ◽

Shuxun Ren ◽

Jae-Hyung Lee ◽

Yun-Hua Esther Hsiao ◽

Xinshu (Grace) Xiao ◽

...

Keyword(s):

Gene Expression ◽

Alternative Splicing ◽

Rna Sequencing ◽

Rna Splicing ◽

Mrna Splicing ◽

Splicing Regulation ◽

Sequencing Analysis ◽

Cell Based Therapy ◽

Alternative Mrna Splicing ◽

Cardiac Maturation

Background: The complexity of transcriptome and proteome is contributed by alternative splicing of mRNA. Altered mRNA splicing is implicated in both development and disease. However, the change of alternative mRNA splicing during cardiomyocytes maturation is unknown, and the regulatory mechanisms remain unexplored. Methods and Results: Using deep RNA-Sequencing, we identified global alternative splicing changes associated with both cardiac development and pathological remodeling in mouse heart. Further, we identified a highly conserved splicing regulator-RBFox1 to be significantly induced during zebrafish, mouse and human cardiac maturation. RBFox1 expression was also detected in cardiomyocytes derived from both mouse and human embryonic stem cells but at much lower levels comparing to adult heart. In zebrafish embryos, inactivation of RBFox1 caused cardiomyocyte maturation defects. Expression of RBFox1 in cultured neonatal cardiomyocytes was sufficient to promote maturation by reducing fetal marker gene expression while increasing calcium handling gene expression including RyR and promoting sarcomere organization. Deep RNA-Sequencing analysis showed that RBFox1 expression promoted alternative splicing in genes involved in calcium cycling, blood vessel development and muscle contraction. Finally, we identified a highly conserved mutually exclusive alternative splicing event of transcription factor MEF2 to be a direct downstream target of RBFox1. Expression of individual MEF2 splicing variants led to different cardiac developmental phenotypes in zebrafish, indicating their different transcriptional activities. Conclusion: Our study provided the first comprehensive analysis of mRNA splicing regulation in heart during post-natal development and heart failure, and identified RBFox1 as a key regulator for alternative RNA splicing during cardiomyocytes maturation. Further exploration of RBFox1 mediated RNA splicing regulation in heart may yield novel insight to the underlying mechanisms of cardiac maturation and new approach to improve cell based therapy for heart diseases.

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E3 Ubiquitin Ligase in Anticancer Drugdsla Resistance: Recent Advances and Future Potential

Frontiers in Pharmacology ◽

10.3389/fphar.2021.645864 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuanqi Liu ◽

Chaojun Duan ◽

Chunfang Zhang

Keyword(s):

Drug Resistance ◽

Drug Targets ◽

Clinical Situation ◽

Primary Treatment ◽

Cancer Drug ◽

Therapeutic Effects ◽

Specific Substrate ◽

Cancer Drug Resistance ◽

Future Potential ◽

Substrate Proteins

Drug therapy is the primary treatment for patients with advanced cancer. The use of anticancer drugs will inevitably lead to drug resistance, which manifests as tumor recurrence. Overcoming chemoresistance may enable cancer patients to have better therapeutic effects. However, the mechanisms underlying drug resistance are poorly understood. E3 ubiquitin ligases (E3s) are a large class of proteins, and there are over 800 putative functional E3s. E3s play a crucial role in substrate recognition and catalyze the final step of ubiquitin transfer to specific substrate proteins. The diversity of the set of substrates contributes to the diverse functions of E3s, indicating that E3s could be desirable drug targets. The E3s MDM2, FBWX7, and SKP2 have been well studied and have shown a relationship with drug resistance. Strategies targeting E3s to combat drug resistance include interfering with their activators, degrading the E3s themselves and influencing the interaction between E3s and their substrates. Research on E3s has led to the discovery of possible therapeutic methods to overcome the challenging clinical situation imposed by drug resistance. In this article, we summarize the role of E3s in cancer drug resistance from the perspective of drug class.

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The role of alternative splicing in cancer drug resistance

Current Opinion in Genetics & Development ◽

10.1016/j.gde.2017.10.001 ◽

2018 ◽

Vol 48 ◽

pp. 16-21 ◽

Cited By ~ 35

Author(s):

Zahava Siegfried ◽

Rotem Karni

Keyword(s):

Drug Resistance ◽

Alternative Splicing ◽

Cancer Drug ◽

Cancer Drug Resistance

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New cancer drug targets identified in adrenocortical carcinoma through gene expression profiling

Endocrine Abstracts ◽

10.1530/endoabs.56.p115 ◽

2018 ◽

Author(s):

Raimunde Liang ◽

Isabel Weigand ◽

Barbara Altieri ◽

Stefan Kircher ◽

Sonja Steinhauer ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Profiling ◽

Adrenocortical Carcinoma ◽

Expression Profiling ◽

Drug Targets ◽

Cancer Drug

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Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200103114556 ◽

2020 ◽

Vol 20 (9) ◽

pp. 779-787

Author(s):

Kajal Ghosal ◽

Christian Agatemor ◽

Richard I. Han ◽

Amy T. Ku ◽

Sabu Thomas ◽

...

Keyword(s):

Drug Resistance ◽

Dna Repair ◽

Fanconi Anemia ◽

Cancer Drug ◽

Drug Resistant ◽

Cancer Drugs ◽

Repair Pathway ◽

Cancer Drug Resistance ◽

Anti Cancer ◽

Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

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