miR-181a: regulatory roles, cancer-associated signaling pathway disruptions, and therapeutic potential

Abstract

Introduction: microRNA-181a (miR-181a) is a crucial post-transcriptional regulator of many mRNA transcripts and noncoding-RNAs, influencing cell proliferation, cancer cell stemness, apoptosis, and immune responses. Its abnormal expression is well-characterized in numerous cancers, establishing it as a significant genomic vulnerability and biomarker in cancer research.

Areas covered: Here, we summarize miR-181a's correlation with poor patient outcomes across numerous cancers and the mechanisms governing miR-181a's activity and processing. We comprehensively describe miR-181a's involvement in multiple regulatory cancer signaling pathways, cellular processes, and the tumor microenvironment. We also discuss current therapeutic approaches to targeting miR-181a, highlighting their limitations and future potential.

Expert opinion: miR-181a is a clinically relevant pan-cancer biomarker with potential as a therapeutic target. Its regulatory control of tumorigenic signaling pathways and immune responses positions it as a promising candidate for personalized treatments. The success of miR-181a as a target relies on the development of specific therapeutics platforms. Future research on miR-181a's role in the tumor microenvironment and the RNA binding proteins that regulate its stability will help uncover new techniques to targeting miR-181a. Further research into miR-181a serum levels in patients undergoing therapy will help to better stratify patients and enhance therapeutic success.

Keywords: Biomarker; cancer; miR-181a; microRNA; microRNA processing; microRNA regulation; microRNA therapeutics; signaling pathways.

Figure 1.

The miR-181a biogenesis pathway following canonical miRNA biogenesis. miR-181 is transcribed by RNA Polll, generating one of three primary transcripts. miR-181a and miR-181b can be transcribed from chromosome 1 or 9. miR-181c and miR-181d are transcribed from chromosome 19. Following miR-181a-1 synthesis, its primary miR-181a/b-1 transcript is cleaved by the drosha-DGCR8 microprocessor complex into individual pre-miR181a/b transcripts and exported into the cytoplasm via Exportin 5-Ran-GTP. In the cytoplasm, DICER-TRBP cleaves the hairpin structure to the mature miR-181a duplex. The mature strand is then loaded onto Argonaut (Ago), and the passenger strand is expelled and sometimes degraded. To facilitate mRNA regulation, the Ago-mature miRNA unit, now termed RNA-induced silencing complex (RISC), is guided to the 3’UTR on target mRNA sequences and facilitates translational repression. Alternatively, mature miR-181a can be exported out of the cell in exosomes and microvesicles. Created in BioRender. Ventura, A. (2024).

Figure 2.

The role of miR-181a in the regulation of TGF-β signaling across cancer types. miR-181a can promote and TGF-β signaling by upregulating tgf-βRI, inhibiting XIAP, an inhibitor of tgf-βRII, and directly inhibiting SMAD7, an inhibitor of tgf-β signaling. Increased TGF-β signaling also leads to SMAD2/3/4 transactivation of miR-181a transcription, SMAD2/3 complexing with pri-miR-181a, and increased processing of pri-/pre-miR181a, elevating mature miR-181a levels. Activin treatment also promotes TGF-β signaling and miR-181a. alternatively, miR-181a can inhibit TGF-β signaling by targeting SMAD2, EGR-1, TGF-βRI, BIM and TGIF2 directly. Alternatively, SMAD2 expression is also affected by LINC01232, which can sponge miR-181a, facilitating the increase of SMAD2. miR-181a is predicted to interact with BMPR1B, a crucial regulator of SMAD signaling. Created in BioRender. Ventura, A. (2024).

Figure 3.

The role of miR-181a in the regulation of wnt signaling across cancer types. In HGSC, miR-181a suppresses the Wnt antagonists SFRP4 and NLK. In ALL, HCC and CRC, miR-181a directly inhibits WIF1, altering cell growth and proliferation. In CRC alone, miR-181a overexpression reduced the wnt target gene expression of COX2, FXD4, and LRP6. miR-181a can also function as a tumor suppressor in the Wnt/β-catenin pathway. In CRC, miR-181a suppresses the wnt signaling activators β-catenin and TCF4. Alternatively, β-catenin and TCF4 bind to the promoter region of MIR181A2B2 leading to increased miR-181a expression. miR-181a is also sponged by lncRNA-SNHG7, leading to GATA6 upregulation in HCC and PTC. Additionally, in HCC miR-181a is directly regulated by Wnt signaling through NLK and SFRP4. Created in BioRender. Ventura, A. (2024).

Figure 4.

(a) The role of miR-181a in regulating PI3K/PTEN signaling across cancer types. To upregulate this pathway, miR-181a directly targets of critical tumor suppressor PTEN in CRC, BC, NB, and HCC. In BC, miR-181a also directly targets NDRG2, resulting in PTEN dephosphorylation and increased AKT phosphorylation. To downregulate this pathway, miR-181a also interacts with several lncRNAs, such as the XIST, CASC2, and MBNL1-AS1. miR-181a also reduces PIK3R3 in CRC, PHLPP2 and INPP4B phosphatases in BC, EPDR1 in BC, and TCL1A expression in GC. miR-181a also directly targets MMP-14 in CML thereby preventing propagation of PAM signaling. (b) The role of miR-181a in the regulation of Ras signaling across cancer types. miR-181a can function as a tumor suppressor by directly regulating Ras isoforms, NRAS and KRAS, in AML, OSCC, and NSCLC. Further, miR-181a inhibits RalA leading to increased cell cycle arrest and apoptosis. Further, miR-181a supplementation has been shown to increase chemo-sensitivity when combined with BRAF inhibitors. As an oncomiR, miR-181a can inhibit RASSF1A thereby preventing the degradation of MDM2 leading to inhibition of P53. In HCC, miR-181a targets CDX2, promoting cell differentiation and enriched stem cell properties. miR-181a also modulates chemoresistance by targeting proteins GAS7 in NSCLC. In BC, miR-181a directly represses Bim, a pro-apoptotic factor that interacts with ERK, thereby promoting cancer progression. (c) The role of miR-181a in the regulation of P38/MAPK signaling across cancer types. miR-181a interacts with DUSP5/6 to enhance TCR signaling. Additionally, miR-181a can regulate p38 MAPK activation by targeting MKP-5 in HCC. Created in BioRender. Ventura, A. (2024).

Figure 5.

(a) The role of miR-181a in the regulation of JAK/STAT signaling across cancer types. miR-181a directly inhibits PIAS3 and SOCS3 in BC. Similarly, in T-LGL and CRLM, miR-181a seems to directly target DUSP6 and SOCS3. A competitive regulatory loop also exists where miR-181a directly inhibits STAT1 and STAT1 binds to the promoter of miR-181a preventing its transcription. (b) The role of miR-181a in the regulation of STING activation and signaling across cancer types. As we report, miR-181a regulates STING activation in high-grade serous cancer and in triple-negative breast cancer thus stimulating innate immune responses. Created in BioRender. Ventura, A. (2024).

Figure 6.

Schematic depicting miR-181a’s oncogenic and tumor suppressive function across numerous signaling pathways in cancer. miR-181a dysregulation can enable cancer cells to acquire hallmark capabilities required by this neoplastic disease [10]. miR-181a can modulate the function of several key molecular pathways, including RB1, Ras, BCL-2, and SRC/VEGF, leading to genomic instability, senescent cells, apoptotic dysfunction, angiogenesis, and an evasion of growth suppressors. miR-181a dysregulation can also lead to the overactivation of other pathways and proteins such as the activation of wnt, SOX2, TGF-β, and Ras/PI3K/Notch across several cancer types. This overactivation can promote stemness, activate invasion and metastasis, and increase proliferation capabilities, respectively. miR-181a dysfunction also impacts cancer epigenetics, causing nonmutational epigenetic reprogramming though the overactivation of H3K27ac methylation CNAs. Additionally, miR-181a overexpression can impact immune regulation through the inhibition of nf-κβ, STAT, and STING signaling. Created in BioRender. Ventura, A. (2024).