Overcoming stemness and chemoresistance in colorectal cancer through miR-195-5p-modulated inhibition of notch signaling

The susceptibility of cancer cells to different types of treatments can be restricted by intrinsic and acquired therapeutic resistance, leading to the failure of cancer regression and remission. To overcome this problem, a combination therapy has been proposed as a fundamental strategy to improve therapeutic responses; however, resistance is still unavoidable. MicroRNA (miRNAs) are associated with cancer therapeutic resistance. The modulation of dysregulated miRNA levels through miRNA-based therapy comprising a replacement or inhibition approach has been proposed to sensitize cancer cells to other anti-cancer therapies. The combination of miRNA-based therapy with other anti-cancer therapies (miRNA-based combinatorial cancer therapy) is attractive, due to the ability of miRNAs to target multiple genes associated with the signaling pathways controlling therapeutic resistance. In this article, we present an overview of recent findings on the role of therapeutic resistance-related miRNAs in different types of cancer. We review the feasibility of utilizing dysregulated miRNAs in cancer cells and extracellular vesicles as potential candidates for miRNA-based combinatorial cancer therapy. We also discuss innate properties of miRNAs that need to be considered for more effective combinatorial cancer therapy.Cells 2020, 9, 29 2 of 32 to confer the ability to acquire CSC properties onto cancer cells, thereby contributing to therapeutic resistance [7]. Moreover, cell-to-cell communication via extracellular vesicles among different types of cells within the cancer microenvironment could affect the efficacy of cancer therapies by delivering miRNAs that regulate various signaling pathways connected to therapeutic resistance [8,9].Combination therapies have been proposed to overcome therapeutic resistance via the combined inhibition of different mechanisms. For example, the combination of cobimetinib and pictilisib was reported to be beneficial for the treatment of colorectal cancer cells. However, resistance is unavoidable even after the combination treatment [10]. Similarly, the simultaneous inhibition of phosphoinositide 3-kinase (PI3K) and a mechanistic target of rapamycin kinase (mTOR) was reported to activate extracellular signal-regulated kinase (ERK), a pro-survival factor, in acute myeloid leukemia [11]. Therefore, it is still necessary to explore new combination strategies to defeat therapeutic resistance. An improved understanding of the cellular basis of cancer therapeutic resistance can further provide promising opportunities to design and develop novel cancer treatment strategies to manage cancers.MicroRNAs (miRNAs) are widely recognized, small, regulatory RNAs modulating numerous intracellular signaling pathways in several diseases, including cancers. Based on the expression levels and intracellular functions of miRNAs, they could act as tumor-suppressive or oncogenic factors in cancer cells [12][13][14]. The abnormal expression of miRNAs is associated with therapeutic resistance in cancer, and the modulation of m...

Section: A Mirna-regulating Notch Receptor 2 and Its Downstream Signamentioning

confidence: 99%

Section: Direct Regulation Of Stemness Factorsmentioning

confidence: 99%

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

Seo

Moeng

Sim³

et al. 2019

“…Consequently, the transcriptions of Notch-targeted genes are activated. The RBPJ-dependent Notch signaling pathway is related with the aggressive CRC tumor phenotype [81]. By negatively regulating the Notch signaling pathway, miR-195-5p decreases the population of CSCs and CRC drug resistance.…”

Section: Mir-195-5pmentioning

confidence: 99%

microRNA: The Impact on Cancer Stemness and Therapeutic Resistance

Jiao

Qian

et al. 2019

Cancer ranks as the second leading cause of death worldwide, causing a large social and economic burden. However, most anti-cancer treatments face the problems of tumor recurrence and metastasis. Therefore, finding an effective cure for cancer needs to be solved urgently. Recently, the discovery of cancer stem cells (CSCs) provides a new orientation for cancer research and therapy. CSCs share main characteristics with stem cells and are able to generate an entire tumor. Besides, CSCs usually escape from current anti-cancer therapies, which is partly responsible for tumor recurrence and poor prognosis. microRNAs (miRNAs) belong to small noncoding RNA and regulate gene post-transcriptional expression. The dysregulation of miRNAs leads to plenty of diseases, including cancer. The aberrant miRNA expression in CSCs enhances stemness maintenance. In this review, we summarize the role of miRNAs on CSCs in the eight most common cancers, hoping to bridge the research of miRNAs and CSCs with clinical applications. We found that miRNAs can act as tumor promoter or suppressor. The dysregulation of miRNAs enhances cell stemness and contributes to tumor metastasis and therapeutic resistance via the formation of feedback loops and constitutive activation of carcinogenic signaling pathways. More importantly, some miRNAs may be potential targets for diagnosis, prognosis, and cancer treatments.

“…MiRNA-215 DTL [59] miR-148a WNT, β-catenin [60] miR-199a/b Gsk3β, Wnt/β-catenin-ABCG2 [61] miR-196b-5p STAT3 [62] miRs-31 EphB2 and EphA2 [63] miR-27a Apaf-1/caspase-9 [64] miR-372/373 Nanog, Hedgehog, NFκB, MAPK/Erk, VDR Jak-STAT, TGF-beta, PI3K-Akt, MAPK. [65,66] miR-137 DCLK1 [67] miR-146a β-catenin [68] miR-195-5p STAT3, BIRC5, BCL2, BCL-XL, SOX2, CD133, RBPJ, Notch2 [62,69] Lung miR-128 AKT/ERK, p38, c-met/PI3K/AKT, VEGF/PI3K/AKT, IL-6-JAK-STAT3 [70][71][72][73] miR-181b Notch2 [74] miR-138 TGFβ [75] miR-5100 Rab6 [76] miR-214 c-MYC [76] miR-708-5p Wnt/β-catenin [77] miR-873 miR-125a-3p…”

Section: Role Of Mirna and Oncogenic Signaling Pathways In Human Cancmentioning

confidence: 99%

Role of miRNA-Regulated Cancer Stem Cells in the Pathogenesis of Human Malignancies

Khan

Ahmed

Elareer

et al. 2019

238

168

Recent biomedical discoveries have revolutionized the concept and understanding of carcinogenesis, a complex and multistep phenomenon which involves accretion of genetic, epigenetic, biochemical, and histological changes, with special reference to MicroRNAs (miRNAs) and cancer stem cells (CSCs). miRNAs are small noncoding molecules known to regulate expression of more than 60% of the human genes, and their aberrant expression has been associated with the pathogenesis of human cancers and the regulation of stemness features of CSCs. CSCs are the small population of cells present in human malignancies well-known for cancer resistance, relapse, tumorigenesis, and poor clinical outcome which compels the development of novel and effective therapeutic protocols for better clinical outcome. Interestingly, the role of miRNAs in maintaining and regulating the functioning of CSCs through targeting various oncogenic signaling pathways, such as Notch, wingless (WNT)/β-Catenin, janus kinases/ signal transducer and activator of transcription (JAK/STAT), phosphatidylinositol 3-kinase/ protein kinase B (PI3/AKT), and nuclear factor kappa-light-chain-enhancer of activated B (NF-kB), is critical and poses a huge challenge to cancer treatment. Based on recent findings, here, we have documented the regulatory action or the underlying mechanisms of how miRNAs affect the signaling pathways attributed to stemness features of CSCs, such as self-renewal, differentiation, epithelial to mesenchymal transition (EMT), metastasis, resistance and recurrence etc., associated with the pathogenesis of various types of human malignancies including colorectal cancer, lung cancer, breast cancer, head and neck cancer, prostate cancer, liver cancer, etc. We also shed light on the fact that the targeted attenuation of deregulated functioning of miRNA related to stemness in human carcinogenesis could be a viable approach for cancer treatment.