Alternative RNA Splicing—The Trojan Horse of Cancer Cells in Chemotherapy
Abstract
:1. Alternative Splicing in Physiological and Neoplastic Processes
2. Lung Cancer
Anticancer Drug Resistance Based on AS in Lung Cancer
3. Breast Cancer
4. Prostate Cancer
5. Head and Neck Squamous Cell Carcinoma
6. Glioma
7. Metastatic Colorectal Carcinoma
8. Hematologic Malignancies
8.1. AS in Lymphoid Malignancies
8.2. AS in Myeloid Malignancies
9. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Malignancy | Gene | Splice Variant | Mutation Type | Drug Resistance | Biological Function | Reference |
---|---|---|---|---|---|---|
NSCLC | PTPMT1 | Exon skipping | SRSF1 target | Radioresistance | Promotes phosphorylation of AMPK PTEN-like mitochondrial phosphatase | [47] |
BIM | Alternative splicing | SRSF1 | Imatinib | [48] | ||
U2AF1 | Loss of function | Gemcitabine, glucocorticoids | Target of the splicing factor quaking (QKI) | [39] | ||
SRSF1 metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) | SRSF1 + ex2 (MCL1L) Alternative 5′SS of exon 2 (BCL-XL) | N/A | Gemcitabine | MNK2 splicing; MCL1 member of BCL2 family splicing to MCL1L long anti-apoptotic variant | [41,42] | |
LUAD | EIF4H | EIF4H + ex5 | Gain of function | Resistance to PI(3)K/AKT/mTOR inhibitors (e.g., AZD8055, BEZ235) | Cancer related genes translation | [49] |
Malignancy | Gene | Splice Variant | Drug Resistance | Biological Action | Reference |
---|---|---|---|---|---|
Breast Cancer | HER2 | P100 of HER2 Δ16-HER2 d16HER2 | Trastuzumab | SRSF3 and hnRNPH1 are associated with splicing regulation of Δ16-HER2. d16HER2 influences tumor initiation and aggressiveness, cancer stem cell properties, epithelial-mesenchymal transition and HER2-positive breast cancer cell susceptibility to trastuzumab | [55,57] |
ECT2 | ECT2-Ex5+ | Doxorubicin | ZRANB2 and SYF2-mediated AS programs converging on ECT2 act in drug resistance | [60] |
Malignancy | Gene | Splice Variant | Mutation Type | Drug Resistance | Biological Function | Reference |
---|---|---|---|---|---|---|
Prostate Cancer | AR | AR-V7 | Cryptique exon 3 inclusion, exon skip | ADT resistance—Enzalutamide, Abiraterone | Activate target gene expression | [84,85] |
SRSF3 SF3B2 U2AF2 | Alternative splicing | Poison exon insertion | AR-V7 induction | Myc interaction and NEPC induction | [90,102,104] | |
EZH2 | EZH2 + ex14 | Exon 14 inclusion (promoted by SF3B3) | AR induction | Enzalutamide | [115,119] |
Malignancy | Gene | Splice Variant | Mutation Type | Drug Resistance | Biological Function | Reference |
---|---|---|---|---|---|---|
Adenoid cystic carcinoma (HNSCC) | FGFR1 | FGFR1v | Premature termination codon at position 147 of intronic segment | Dovitinib | Mediate FGF/FGFR1-independent function through the AXL/AKT signaling axis | [149] |
OSCC | SRSF3 | SRSF3ex4 | Long isoform with exon 4 encodes a truncated SRSF3 protein | Paclitaxel | Increases the expression of c-Jun, cyclin D1, cyclin D3, CDC25A and E2F1, and accelerates cell growth | [58] |
Malignancy | Gene | Splice Variant | Mutation Type | Drug Resistance | Biological Function | Reference |
---|---|---|---|---|---|---|
mCRC | VEGFA | VEGFA145b | Differential splicing of the 3′ distal site of exon 8 | Bevacizumab | Act as a reservoir of angiogenic growth factors in the tumor stroma | [183] |
TIA-1 | sTIA-1 flTIA-1 | Exon 5 exclusion leading to truncated protein | Anti-VEGF antibodies | Alters both co-transcriptional and post-transcriptional RNA processing | [184] |
Malignancy | Gene | Splice Variant | Mutation Type | Drug Resistance | Biological Function | Reference |
---|---|---|---|---|---|---|
CLL | SF3B1 | SF3B1-ΔHEAT | Deletions in HEAT domains | Fludarabine | Splicosome factor | [194] |
T-ALL, cALL (both T- and B-cell) | FPGS | FPGS-ES(12);IR(8) | Exon 12 skipping; intron 8 partial retention | Methotrexate Dexamethasone, Mitoxanthrone, Prednisolone | Intracellular modification of MTX | [198,199,200] |
ALL | GR | GRβ | Downstream acceptor site in exon 9 | Glucocorticoids | Inactive GC receptor; dominant negative isoform | [38] |
P53 | P53β | Exon 9β inclusion | Glucocorticoids | Higher expression in resistant cells | [39] | |
AML | dCT | dCT-ΔEx2–6 | Missing exons 2–6 (deletions) | Cytarabine | Enzyme, which activates Cytarabine | [214,215] |
TET2 | TET2-ES(2) | Skipping of exon 2 | Cytarabine | [213] | ||
P53 | P53β/γ | Alternative splicing of exon 9β or 9γ | Doxorubicin | Better prognosis/active tumor suppressor | [221] | |
Bcl-x | Bcl-xs | Alternative splicing | Multiple drugs | Altered apoptosis; loss of bcl-xs leads to worse RFS and OS | [223] |
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Mehterov, N.; Kazakova, M.; Sbirkov, Y.; Vladimirov, B.; Belev, N.; Yaneva, G.; Todorova, K.; Hayrabedyan, S.; Sarafian, V. Alternative RNA Splicing—The Trojan Horse of Cancer Cells in Chemotherapy. Genes 2021, 12, 1085. https://doi.org/10.3390/genes12071085
Mehterov N, Kazakova M, Sbirkov Y, Vladimirov B, Belev N, Yaneva G, Todorova K, Hayrabedyan S, Sarafian V. Alternative RNA Splicing—The Trojan Horse of Cancer Cells in Chemotherapy. Genes. 2021; 12(7):1085. https://doi.org/10.3390/genes12071085
Chicago/Turabian StyleMehterov, Nikolay, Maria Kazakova, Yordan Sbirkov, Boyan Vladimirov, Nikolay Belev, Galina Yaneva, Krassimira Todorova, Soren Hayrabedyan, and Victoria Sarafian. 2021. "Alternative RNA Splicing—The Trojan Horse of Cancer Cells in Chemotherapy" Genes 12, no. 7: 1085. https://doi.org/10.3390/genes12071085