miR-17: from developmental regulatory hub to molecular engine driving tumourigenesis

The core mechanism by which miR-17 drives MT progression lies in its coordinated targeting and suppression of multiple key tumour suppressor genes controlling cell cycle and survival signalling pathways, thereby establishing a potent oncogenic regulatory network. Cell cycle disruption is a key feature of tumourigenesis, miR-17 directly influences cell cycle progression by interfering with cyclin-dependent kinase (CDK) cyclin-CDK complexes and associated signalling pathways.p21 and p27 are required CDK inhibitors.miR-17 promotes cell growth in haematological malignancies such as CML and BCL ( 75 ), as well as in solid tumours including nasopharyngeal carcinoma ( 76 ) and OS ( 77 ), By inhibiting p21, miR-17 may also simultaneously suppress p21 and TP53-induced Nuclear Protein 1(TP53INP1), thereby synergistically promoting GC cell proliferation and inhibiting apoptosis ( 78 ). Retinoblastoma 1(RB1)is another core protein regulating G1 progression and a classic tumour suppressor. The RB1 tumour suppressor negatively regulates the cell cycle and is inactivated in numerous human tumours. Overexpressed miR-17 directly binds to the 3’UTR of RB1 mRNA, thereby reducing RB1 translation and consequently diminishing RB1 protein expression ( 79 ). Liu et al. discovered that ( 80 ) miR-17 expression positively correlates with SRY-Box Transcription Factor 4(SOX4) expression in PC patients, whilst negatively correlating with RB1 expression. Mechanistically, SOX4 transcribes to upregulate miR-17 expression within PC cells, subsequently directly downregulating RB1 protein. This establishes a functional axis of ‘SOX4 → miR-17 → RB1’, thereby promoting the proliferation, migration, and invasion of PC cells. miR-17 further modulates cell cycle progression via core driver proteins and CDKs. In BC cells, the cyclin D/cyclin-dependent kinase 4 and 6 (CDK4/6) and retinoblastoma (RB) pathways play a crucial role in the proliferation of normal breast tissue, particularly in epithelial cell growth. Asberjer et al. ( 81 ) discovered that downregulating miR-17 inhibits CDK4/6 activity, hereby suppressing the proliferation of BC cells and inducing G1 cell cycle arrest. Concurrently, research by Yu et al. ( 82 ) demonstrated that miR-17 inhibits BC cell proliferation by suppressing the translation of cyclin D1. Furthermore, Wang et al. ( 83 ) discovered that knockdown of the LncRNA NHG16 suppressed cyclin D1 expression by sponging miR-17 in a small-interference RNA(SiRNA)- dependent manner, thereby inhibiting the development of oralsquamous cell carcinoma (OSCC)both in vitro and in vivo . Similarly, research by Huan et al. ( 84 ) confirmed that miR-17 negatively regulates the cell cycle in head and neck squamous cell carcinoma (HNSCC) by directly targeting Cyclin G2(CCNG2), thereby increasing the proportion of cells in the G2/M phase and reducing the proportion in the S phase. Hu et al. ( 85 ) discovered that miR-17 expression was elevated in endometrial tissue from patients with adenomyosis, potentially influencing apoptosis and cyclin expression by targeting PTEN regulation. miR-17 also influences the cell cycle through key signalling pathways such as Wnt/β-catenin and PI3K/AKT. For instance, Sun et al. ( 86 ) observed that increasing downregulation of miR-17, accompanied by elevated Phosphorylated Akt (P-Akt) and Akt expression, enhanced the survival and migration rates of glioblastoma (GBM) cells. Concurrently, research by Mu et al. ( 87 ) demonstrates that the Wnt/β-catenin signalling pathway is crucial for regulating cell proliferation and differentiation. By upregulating miR-17, it mediates the Wnt/β-catenin pathway to exert a proliferative effect on cells. Furthermore, Yu et al. ( 88 ) demonstrated that miR-17-activated Wnt/β-catenin pathways promote the progression of liver fibrosis. Yuan et al. ( 89 ) discovered that miR-17, upregulated via the LncRNA miR-17HG, promotes CRC cancer progression by activating the Wnt/β-catenin signalling pathway. Similarly, Chen et al. ( 90 ) discovered that miR-17 downregulation inactivates Wnt/β-catenin signalling by targeting kinesin-like motor protein family member 23 (KIF23), thereby alleviating apoptosis and fibrosis induced by high glucose in human mesangial cells.

Despite advances in cancer prevention, early detection, and treatment, cancer remains a major unresolved medical challenge worldwide. In 2022, nearly 20 million new cancer cases were diagnosed globally, with approximately 9.7 million deaths. China recorded 4.8247 million new cases and 2.5742 million deaths, ranking first in the world for both metrics ( 1 ). The five leading causes of cancer deaths in China are lung cancer, liver cancer (LC), GC, CRC, and oesophageal cancer (EC). Among these, LC mortality rose from third place in 2018 to second place in 2022 ( 2 ). The global incidence of cancer continues to increase, placing pressure on public health systems ( 3 ). The initiation and progression of MT are primarily driven by dysregulation of gene expression, particularly within key regulatory pathways governing cell proliferation, survival, and apoptosis ( 4 ). Despite advances in understanding molecular mechanisms, the complexity and heterogeneity of cancer remain major challenges for effective treatment. However, approximately 40% of cancer deaths are associated with controllable risk factors. By managing these risks and promoting early diagnosis and precision treatment, the burden of cancer can be effectively reduced ( 5 ). NcRNAs, including miRNAs, lncRNAs, and circRNAs, have garnered significant attention due to their pivotal roles in regulating gene expression and tumour behaviour ( 6 ). Among ncRNAs, miRNAs are the most extensively studied. They play a central role in regulating key biological processes in cancer, including cell proliferation, apoptosis, migration, and invasion ( 7 ). miRNAs constitute a class of endogenous single-stranded ncRNAs ranging from 19 to 25 nucleotides in length. Characterised by high conservation, developmental regulation, and tissue specificity, they primarily function by complementary pairing between their seed sequences and the 3’ untranslated regions (3’UTRs) of target messenger RNA (mRNA). This interaction facilitates mRNA degradation or translation inhibition, thereby regulating gene expression at the post-transcriptional level ( 8 ). miR-17 is a prototypical oncogenic miRNA that plays a pivotal role in the initiation and progression of various malignancies, including lymphoma, lung cancer, CRC, and BC. Through mechanisms such as targeting tumour suppressor genes, regulating cell cycle and signalling pathways, and participating in ncRNA cross-regulatory networks, it acts as a key driver of tumour progression ( 9 ). Among these, miR-17-5p is a core member of the miR-17–92 gene cluster, a classic oncogenic miRNA cluster identified around 2005. This cluster comprises six mature miRNAs, including miR-17-5p, miR-18a, and miR-19a ( 10 , 11 ). The mature sequences of miR-17-3p and miR-17-5p are 5’-CAAAGUGCUUACAGUGCAGGUAG-3’ and 5’- UGUGCUGCUUUCUUGGGUCGG-3’ ( 12 , 13 ). The human miR- 17 cluster is located at chromosome 13 long arm, region 3, band 1, subband 3(13q31.3). Its biogenesis process begins with transcription by RNA polymerase II, yielding primary miRNA(pri-miR)-17–92 containing multiple hairpin structures ( 14 ).Subsequently, within the cell nucleus, the pri-miR-17–92 transcript is cleaved by the microprocessor complex (Drosha ribonuclease III/DGCR8) into a precursor of ~70 nt, pre-miR-17 ( 15 ).Subsequently, pre- miR-17 forms a trimer with (Ras-related nuclear protein-guanosine triphosphate) Exportin-5/Ran-GTP and is transported to the cytoplasm via the nuclear pore complex. Within the cytoplasm, Dicer nucleases recognise the stem-loop structure of pre-miR-17, cleaving it to generate a double-stranded complex of approximately 22 nt comprising miR-17-5p and miR-17-3p.Ultimately, the double- stranded complex binds to the Argonaute protein(AGO protein), where miR-17-3p is degraded while miR-17-5p is retained and assembled into the RNA-induced silencing complex (RISC). This complex binds to the 3’ UTR of the target mRNA via complementary base pairing, thereby regulating the expression of the target gene ( 16 , 17 ). Research has revealed that miR-17inhibits osteoblast differentiation by targeting the SRY-box transcription factor 6 (Sox6), thereby providing a potential therapeutic target for the treatment of orthopaedic conditions such as osteoporosis and osteoarthritis ( 18 ). miR-17 inhibits the progression of osteoarthritis by reducing chondrocyte apoptosis and extracellular matrix degradation through targeted suppression of Enhancer of Zeste Homolog 2( EZH2) ( 19 ). Concurrently, miR-17 alleviates pathological cardiac fibrosis by targeting BCL2/adenovirus E1B 19 kDa protein-interacting protein 3(BNIP3), thereby reducing mitochondrial autophagy in cardiomyocytes ( 20 ). Furthermore, inhibition of miR-17 alleviates acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by modulating mitochondrial autophagy mediated by mitochondrial fusion protein 2(Mfn2) ( 21 ). More importantly, miR-17 has the potential to selectively target multiple genes, thereby inhibiting tumour growth. Its regulation of signalling pathways constitutes a key factor in tumour development, making it a promising candidate for an important therapeutic target in cancer treatment. This paper analyzes the significance of miR-17 in the field of cancer therapy, elucidating its multifaceted roles in tumor cell invasion, metastasis, proliferation, apoptosis, and drug resistance, to provide a reference for cancer treatment.

Research into miR-17 across various tumours represents a dynamic field with multifaceted potential for future studies and clinical applications. miR-17 and its specific miRNAs offer promising therapeutic targets for developing novel treatments for diverse cancers. The expression levels of miR-17 may serve as diagnostic and prognostic biomarkers for various cancers. Continued investigation into its clinical significance and validation within large patient cohorts is of paramount importance. Understanding the mechanisms by which miR-17 promotes metastasis and the role of EMT in various tumours facilitates the development of therapies targeting these processes, thereby improving patient outcomes. Exploring potential synergies between miR-17-targeted therapies and existing cancer treatments, such as chemotherapy or immunotherapy, holds promise for enhancing the efficacy of current therapeutic approaches. Tailoring treatment strategies to a patient’s specific miRNA expression profile may yield more personalised and effective therapeutic approaches. Regarding drug resistance, further research into miR-17 and its impact on drug response, alongside the development of personalised therapies based on patients’ miRNA profiles, could enable treatments that modulate miR-17 expression or activity. This approach holds promise for overcoming chemotherapy resistance and enhancing therapeutic outcomes across diverse patient populations. miR-17 drives malignant progression in tumours through a complex network of synergistic interactions at multiple levels. Future research should delve deeper into the distinct and overlapping functions of miR-17 within specific tumour contexts, while developing targeting strategies with enhanced selectivity and reduced toxicity. Concurrently, elucidating its precise role in immune regulation within the tumour microenvironment will open new avenues for immunotherapy combination approaches. Further investigation into how miR-17 promotes chemotherapy resistance and its impact on mitochondrial homeostasis may reveal novel therapeutic targets. A deeper understanding of miR-17 as a “signalling hub” will undoubtedly advance the era of RNA-based precision cancer diagnosis and treatment.

Despite ongoing advances in cancer treatment technologies, chemotherapy remains the cornerstone therapy for advanced cancers. However, chemotherapy resistance continues to be one of the key obstacles limiting treatment efficacy ( 109 , 110 ). Recent studies indicate that miRNAs play an increasingly significant role in regulating cancer cells’ therapeutic response, particularly in the mechanisms of chemotherapy resistance. By targeting and modulating the expression of relevant genes, miRNAs directly influence tumour cells’ sensitivity to chemotherapeutic agents ( 111 ). Its core functional mechanism operates as follows: miR-17, acting as a post- transcriptional regulator of gene expression, can bind to the 3’-UTR region of target genes. This binding inhibits mRNA translation or promotes mRNA degradation, thereby modulating key cellular pathways such as apoptosis, proliferation, and DNA damage repair. Ultimately, this mediates chemoresistant or chemosensitive phenotypes ( 112 ). MiR-17 plays a complex role in regulating chemotherapy sensitivity and resistance across multiple cancer types. For instance, miR-17 mediates resistance to chemotherapeutic agents (such as cisplatin) and targeted therapies in various tumours by regulating multiple key molecules involved in apoptosis and survival, including Bim and PTEN ( 113 ). Concurrently, Weng et al. ( 114 ) discovered that the traditional Chinese medicine compound oridonin can induce apoptosis by inhibiting miR-17 and reverse chemoresistance by de-suppressing Bcl-2 Interacting Mediator of Cell Death Short Form (Bim-S). Furthermore, research by Shuang et al. ( 115 ) confirmed that miR-17 suppresses Bim expression by directly binding to the Bim 3′-UTR, thereby reducing the sensitivity of human OC SKOV3-TR30 cells to paclitaxel. Similarly, Dai et al. ( 116 ) discovered that MYC/miR-17 form a positive feedback loop to maintain low Bim expression, thereby permitting cell proliferation. STAT3 and miR-17 form a positive feedback loop: STAT3 upregulates miR-17, which in turn upregulates STAT3, collectively mediating tumour cell resistance to Mitogen-Activated Protein Kinase Kinase(MEK)inhibitors.”miR-17 may also regulate other drug resistance pathways. For instance, Wan et al. ( 117 ) observed that interference with miR- 17 potentially aids in overcoming glucocorticoid resistance in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Concurrently, research by Jiang et al. ( 118 ) demonstrated that the miR-17 family regulates cisplatin resistance and metastasis in NSCLC by targeting TGF-β receptors. The role of miR-17 in cancer chemotherapy and radiotherapy highlights its complex regulatory functions, which are influenced by tumour type, therapeutic agents, and cancer cell-specific characteristics. Specifically, the expression of miR-17 across different cancer types may be influenced by multiple factors, including the drug resistance characteristics of tumour cells and alterations within the tumour microenvironment. Therefore, the mechanism of action of miR-17 as a potential therapeutic target warrants further investigation. In summary, miR-17’s dual role in chemotherapy and radiotherapy underscores its potential as a therapeutic target, with implications for overcoming drug resistance and guiding personalized treatment strategies. An in-depth investigation into the mechanisms of miR-17 and its interactions with chemotherapeutic agents and radiotherapy will provide valuable insights for overcoming drug resistance in cancer treatment and offer new directions for future therapeutic strategies.

As a prototypical oncogenic miRNA, miR-17 plays a central driving role in malignant tumours such as lymphoma, lung cancer, CRC, and BC. It inhibits apoptosis and promotes G1/S transition to drive unlimited proliferation of tumour cells by targeting tumour suppressor genes and cell cycle regulators. Concurrently, it targets molecules associated with EMT and activates key signalling pathways, including PI3K/AKT, Wnt/β-catenin pathways, to enhance tumour cell migration and invasive capacity. It may also participate in ncRNA cross-regulatory networks, being adsorbed by LncRNAs and circRNAs as molecular sponges or regulating their stability and biogenesis. This further amplifies OE and induces tumour cell resistance to chemotherapy and radiotherapy, ultimately synergistically promoting tumour angiogenesis and microenvironmental remodelling. In clinical applications, miR-17 demonstrates potential for early cancer diagnosis, particularly serving as a non-invasive biomarker in GC and lung cancers ( 56 ). When targeted therapeutically, inhibiting miR-17 expression enhances the efficacy of chemotherapy or targeted therapies while improving patient prognosis ( 133 ). However, its clinical application remains challenged by factors such as incomplete elucidation of its mechanisms of action. Future research must further unravel its molecular regulatory networks to advance precision diagnostics and therapeutic translation. In recent years, an increasing number of studies have further revealed the regulatory roles and clinical application potential of miR‑17 in different tumors, which provide a theoretical basis for targeted therapy and biomarker research ( 134 – 146 ).

Detection of miR-17 in patient serum, plasma, or exosomes demonstrates its potential as a non-invasive liquid biopsy biomarker for early cancer diagnosis and prognostic assessment. Studies by Li et al. ( 119 ) revealed that miR-17 exhibits elevated expression in serum samples from both GC patients and those with intestinal metaplasia, compared to healthy controls. Consequently, serum miR-17 demonstrates discriminatory power between GC and intestinal metaplasia patients versus healthy controls, suggesting that the miR-17 cluster holds potential as a serum biomarker for the early detection of GC. Similarly, miR-17 is significantly elevated in the plasma of CRC patients and may serve as a biomarker for CRC screening ( 120 ). Research has confirmed that plasma levels of miR-17 are significantly elevated in patients with Pa, ESCC, and GC compared to control volunteers. Furthermore, in these three cancer types, plasma concentrations of miR-17 in post-operative samples were markedly lower than those in pre-operative samples ( 121 – 123 ). This confirms that miR-17 can serve as a biomarker for the screening and monitoring of MT. The ASO inhibitor of miR-17 has demonstrated antitumour effects in clinical models. For example, Wan et al. ( 124 ) found that ASO may inhibit proliferation and induce apoptosis in lung cancer cells by suppressing the oncogenic miR-17. Furthermore, Han et al. ( 125 ) discovered that circ LONP2, formed from exons 11–12 of LONP2, enhances the in vitro invasive capacity of cancer cells, with its core function dependent on regulation via the miR-17 pathway. Targeting circLONP2 through anti-AS inhibition significantly reduces the in vitro invasive and metastatic capabilities of CRC cells. Concurrently, Locked Nucleic Acid (LNA) gapme RASOs induce ribonuclease H-mediated degradation of the MIR17 Host Gene (MIR17HG) primary transcript, thereby blocking the biosynthesis of the miR-17and inhibiting CRC tumour growth ( 126 ).10.2.2 Targeted miRNA processing and functional complexes. Developing small-molecule drugs to disrupt the binding of miRNA to Argonaute (AGO) proteins or interfere with their biogenesis represents another significant avenue of research. Among humans, AGO2 is considered the sole cleaver, whilst AGO3 is scarcely capable of cleaving RNA ( 127 ). Argonaute2 protein is crucial for embryonic development, stem cell maintenance, and cellular differentiation. Under stable and prolonged overexpression, AGO2 induces the production of multiple miRNAs in 7T cells, such as those within the let-7 family. On the other hand, the expression of numerous miRNAs remains insensitive to elevated Argonaute levels, with miR-17 even being downregulated. This downregulation may result from let-7-mediated suppression of Myc expression, as Myc actively regulates the transcription of miRNA clusters ( 128 ). Growth Factor Receptor-Bound Protein 2(GRB2) enhances miR-17 expression. GRB2 forms a direct interaction with AGO2, mediated by the Src Homology 3 domain (SH3). Complex formation is entirely dependent on GRB2 concentration. Therefore, strict regulation of GRB2 expression is essential to eliminate abnormal oncogene expression and cellular proliferation ( 129 ). Research by Iosue et al. revealed that silencing AGO2 impairs the function of miR-17 and promotes cellular differentiation ( 130 ). These studies indicate that targeting AGO2 or its regulatory factors can indirectly modulate the miR-17 functional network. Combining miR-17 inhibitors with standard chemotherapy, radiotherapy, or immune checkpoint inhibitors holds promise for overcoming resistance and enhancing therapeutic efficacy. For instance, Sun et al. ( 131 ) discovered that the miR-17 targeting METTL14 (methyl transferase-like protein 14 in colorectal cancer)/miR-17/MFN2 (mitochondrial fusion protein 2) signalling axis can restore the chemotherapeutic sensitivity of CRC cells to 5-FU. Concurrently, Weng et al. ( 114 ) observed that elevated miR-17 expression diminishes cellular sensitivity to etoposide; downregulating miR-17 expression via miRNA inhibitors or oridone restores chemotherapy sensitivity to etoposide. Similarly, research by Dai et al. ( 116 ) revealed that STAT3-regulated miR-17 serves as a key driver of resistance to MEK inhibitors such as AZD6244. Inhibiting miR-17 reverses the sensitivity of resistant cells to AZD6244 by inducing Bim expression and Poly (ADP-Ribose) Polymerase (PARP) cleavage. Concurrently, Yin et al. ( 132 ) discovered that let-7 and miR-17 respectively influence self- renewal and gefitinib resistance by regulating Myc and Cyclin-Dependent Kinase Inhibitor 1A(CDKN1A). On the one hand, low let-7 levels promote Myc expression to aid in maintaining an undifferentiated state. On the other hand, elevated miR-17 levels reduce CDKN1A expression, thereby contributing to the preservation of proliferative potential. Consequently, the combined effects of low let-7 and high miR-17 regulate self-renewal by promoting cancer stem cell expansion, thereby conferring protection against gefitinib-induced cytotoxicity and generating gefitinib resistance.

MiR-17 plays a pivotal role in regulating apoptosis and cell survival. Its function is mediated by targeting the Bcl-2 protein, the apoptotic effector proteins Caspase-3 and Caspase-9, and the upstream pro-apoptotic factor Bim Its action exhibits a high degree of environmental and tissue specificity: In most scenarios, it exerts anti-apoptotic effects by either suppressing apoptosis through promoting Bax and Caspase-3/9 expression whilst downregulating Bcl-2 levels, or by diminishing apoptosis rates via targeted inhibition of Toll-like receptor 4(TLR4) to attenuate the nuclear factor kappa-B( NF-κB) signalling pathway ( 101 ). Alternatively, exosome-mediated uptake of circZNRF1 may regulate Bcl-2 binding to exert anti-apoptotic effects ( 102 ).It can also inhibit the survival factor insulin-like growth factor 1(IGF-1) from upregulating Bcl-2 and downregulating Caspase-3 ( 103 ), or affect the expression of PTEN and apoptosis-related proteins to promote cell proliferation ( 104 ). Under specific conditions, it exhibits pro-apoptotic effects, such as inhibiting Bcl-2 expression and activating Caspase-3 cleavage ( 105 )or downregulating Bcl-2 and STAT3 expression to enhance apoptosis ( 98 ).It may also synergise with miR- 16 to induce apoptosis via the Caspase-3 pathway ( 106 ). Furthermore, miR-17 enhances cellular viability by directly suppressing Bim ( 107 ) whilst oncogene-driven miR-17 inhibits Bim to shield cells from apoptosis ( 108 ).This bidirectional regulation underscores its pivotal role as a central regulatory hub ( 80 ).Bidirectional regulation within complex networks and disease-specific functional clusters is deeply integrated into broader signalling networks, potentially yielding bidirectional or even contradictory outcomes depending on cell type and microenvironmental signalling. .