Regulatory Functions of microRNAs in Cancer Stem Cells: Mechanism, Facts, and Perspectives

Abstract

Cancer represents a significant global health hazard marked by elevated morbidity and mortality rates. Furthermore, the majority of tumor therapies encounter challenges, including metastasis, recurrence, and drug resistance. Consequently, it is essential to identify a specific and efficient tumor treatment approach. In recent years, the ongoing investigation and comprehension of tumors have led to significant attention towards cancer stem cells (CSCs). CSCs can facilitate tumor progression via self-renewal, differentiation capabilities, and multidrug resistance. Their function as a fundamental contributor to tumor heterogeneity, drug resistance, recurrence, and metastasis has emerged as a significant focus in cancer therapy research. In recent years, microRNAs (miRNAs) have been identified as crucial post-transcriptional regulators in biological processes, including chemosensitivity, self-renewal, apoptosis, invasion, and metastasis of cancer stem cells (CSCs). This paper systematically reviews the molecular mechanisms through which miRNAs influence the characteristics of cancer stem cells by targeting essential genes (e.g., SOX2, EGFR, c-Met) and modulating signaling pathways, including Wnt/β-catenin, Notch, Hedgehog, and PI3K/Akt. Furthermore, we investigated the viability of miRNAs as non-invasive biomarkers for cancer diagnosis and prognosis evaluation, examined the similarities and attributes of pivotal miRNAs in modulating cancer stem cell functionality, and deliberated on therapeutic approaches stemming from miRNA regulation of cancer stem cell activity. We anticipate that this research will yield novel insights into targeted cancer therapy.

Keywords: biomarkers; cancer stem cells; chemotherapy resistance; miRNAs; signaling pathways.

Figure 1

Molecular mechanisms of miRNAs regulating radiochemotherapy resistance and self-renewal in CSCs. (A) Molecular mechanisms of miRNAs regulating chemoresistance and radioresistance in CSCs. miR-339-5p, miR-508-5p, miR-7-5p, miR-29b-3p, miR-449a, and miR-186 downregulation promotes the expression of oncogenes such as SOX2, Bcl-2, c-Myc, and Nanog, which in turn leads to chemoresistance and radiotherapy resistance. miR-206 downregulation in multiple cancer cells promoted chemoresistance through activation of the Wnt/β-catenin signaling pathway; miR-181a activated this pathway through inhibition of SFRP4 and enhanced chemoresistance in CSCs. p53 mutations caused chemoresistance through the miR-34a/LRPPRC/MDR1 signaling pathway. Downregulation of miR-497 promoted gemcitabine resistance in CSCs by enhancing NFκB1 activity. Overexpression of miR-379-5p inhibited radiotherapy resistance in CSCs by regulating the RAD18/Polη axis. miR-495 downregulation promoted the EMT phenotype through upregulation of GRP78, resulting in radiotherapy resistance. miR-485-5p deregulation enhanced chemoresistance by modulating the KRT17/integrin/FAK/Src/ERK/β-catenin signaling pathway to enhance chemoresistance. Overexpression of miR-1275 inhibits the MDK/AKT signaling pathway and attenuates chemoresistance. miR-378a-3p/miR-378d promotes chemoresistance in CSCs through inhibition of DKK3 and NUMB. miR-148a deregulation enhances chemoresistance in CSCs through upregulation of PXR. (B) Molecular mechanisms by which miRNAs regulate self-renewal of CSCs. miR-2117 downregulation increases SOX2 expression. miR-194 attenuates the regulation of RAC1 and PRC1 and activates the Wnt/β-catenin signaling pathway. miR-342-3p deregulation enhances CSCs by inhibiting PTEN and promoting HDAC7 self-renewal. miR-130b-5p was negatively correlated with ELK1, which is associated with self-renewal of CSCs. Downregulation of miR-203 promoted the expression of self-renewal-associated factors GATA6, survivin, and Bmi-1. miR-630 attenuated the inhibition of PRKCI, leading to the activation of the Hedgehog signaling pathway. miR-486-5p was downregulated, activating the p85/AKT pathway, Fox01, Sirt1 expression, and enhanced CSC self-renewal. lncRNA UCA1 regulates CSC self-renewal by inhibiting the microRNA-122-5p/SOX2 axis. miR-182 silencing induced by DNA hypermethylation targets BCL2 and HOXA9 and promotes CSC self-renewal.

Figure 2

Molecular mechanisms by which miRNAs regulate invasiveness, proliferation, apoptosis, and metastasis; act as biomarkers; and influence the cell cycle in CSCs. (A) MiR-128-3p downregulation activates Wnt signaling pathway and boosts NEK2 expression. The FUS/circZEB1/miR-128-3p/LBH feedback loop contributes to CSC malignancy via TNF-α-mediated NF-κB signaling. Through miR-27b-5p adsorption, lINC01234 increases CSC invasiveness and SIRT5 expression. miR-7-5p reduces Smo and Hes1 inhibition and promotes Hedgehog signaling. CSC migration and invasiveness are adversely correlated with miR-9-5p and NUMB expression. miR-210 inhibits STMN1 expression to impair cellular flexibility and enhance CSC invasiveness. MKL-1 targets CD44, EpCAM, and miR-17-5p promoters to regulate CSC characteristics, while miR-17-5p inhibits MKL-1 production, creating a negative feedback loop. miR-196a-5p inhibits Smad4 and FOXO1 to increase CSC invasiveness. (B) Downregulating miR-145-5p increased TCTP and BCL-2 and decreased BAX and CASP3 expression, lowering CSC apoptosis. miR-146b-3p targeted MAP3K10 to regulate DYRK2 and GLI2 expression, which affected the Hedgehog signaling pathway. miR-21/miR-21-5p upregulated OCT4, SOX2, NANOG, BCL-2, and CCND1 while inhibiting BAX, KLF3, and CASP3, which promoted CSC proliferation and reduced apoptosis. miR-873 dysregulation increased PLEK2 expression, which stimulated the PI3K/AKT pathway and decreased CSC apoptosis. By competitively binding to miR-202-5p, lncRNA NORAD enhances the expression of its target gene ANP32E, which increases CSC proliferation and decreases apoptosis. (C) MiR-101 downregulation enhances ANXA2 expression, activates the ERK pathway, and suppresses EGR1 expression, which negatively feedbacks on miR-101 transcription. miR-7 deregulation increases KLF4 and RELA expression, which upregulates ESAM and boosts CSC migration. Downregulation of miR-148/152 family members enhances ITGA5 expression and CD44⁺EpCAM. Downregulation of miR-139-5p promotes E2-2 and IGF-1R expression, activating Wnt/β-catenin/TCF7L2 and IGF-1/IGF-1R pathways for CSC migration. Downregulation of miR-145-5p led to increased COL4A3 expression and Wnt/β-catenin pathway activation. SLCO4A1-AS1 competes with miR-150-3p to upregulate SLCO4A1 and enhance CSC migration. (D) Downregulation of miR-637 increases WASH, IL-8, Nanog, and SOX4/9 expression. miR-638 blocks ZO-1 and VE-cadherin. miR-1260b suppresses CASP8, caspase-3, and PARP and enhances cancer cell proliferation and metastasis. miR 23a-3p suppresses APAF1. miR-221/222 promotes Akt expression and suppresses p27, p57, and PTPµ expression. (E) miR-302a/d downregulation increases E2F7 and its downstream signaling pathway, speeding CSCs from G1 to S phase. miR-449b promotes G1-to-S phase cell transition by downregulating CCND1 and E2F3 expressions. miR-92a-3p inhibits LATS1 to upregulate TAZ and downregulate E-cadherin and facilitates G1-to-S-phase cell transition. miR-338-5p promotes G0/G1-to-S and G2/M cell transition by upregulating BAK and BIM.