With increasing rates of morbidity and death worldwide, RCC is one of the most aggressive urogenital cancers [1]. RCC is the tenth most frequent cancer in men, with about 432,000 new cases and 180,000 deaths recorded in 2020, according to global cancer statistics [2]. About 75 percent of all RCC cases are ccRCC, making it the most common histological subtype. Papillary RCC (pRCC) and chromophobe RCC (chRCC) make up 15–20% and 5% of cases, respectively [3]. Patients with ccRCC continue to have a poor prognosis, mostly because of high rates of metastasis or recurrence and difficulties in obtaining an early diagnosis. The principal treatment for localized ccRCC is still radical nephrectomy. But in as many as one-third of instances, the first diagnosis is made at a metastatic stage, making surgery impossible [4]. Furthermore, around 20–30% of patients experience relapse within two years of undergoing radical nephrectomy, with most showing significant resistance to both chemotherapy and radiation therapy [5]. Over recent decades, advances in targeted and immunotherapy have expanded treatment options for ccRCC patients. Despite these advancements, therapeutic efficacy remains limited for advanced or metastatic ccRCC, largely due to the complexity and heterogeneity of the TME. This underscores the urgent need to investigate the molecular mechanisms underlying ccRCC tumorigenesis and progression, particularly the dynamic characteristics of the TME, to identify novel biomarkers and therapeutic targets.
A complex biological process involving gene mutations, genomic instability, and epigenetic alterations leads to the development of ccRCC [6]. The von Hippel-Lindau (VHL) gene is one of the important genes linked to the pathophysiology of ccRCC and is commonly mutated in this cancer type. VHL mutations cause hypoxia-inducible factors (HIFs) to become active, which changes the expression of angiogenic factors such platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) [7]. The mammalian target of rapamycin (mTOR) signaling pathway is also triggered by VHL mutations, which increases HIF activity and encourages angiogenesis, ultimately propelling the development of ccRCC. These discoveries have aided in the creation of medications that target the mTOR pathway, PDGF/PDGF receptor (PDGFR), and VEGF/VEGF receptor (VEGFR) [8].
Despite these advances, reliable diagnostic and prognostic biomarkers for ccRCC have yet to be established for clinical use. Recently, the role of epigenetics in ccRCC, particularly non-coding RNAs (ncRNAs), has garnered significant attention. Many ncRNAs have been found to exhibit aberrant expression in various tumors, highlighting their critical role in tumor initiation and progression [9]. Exploring the functions of ncRNAs further may pave the way for improved early diagnosis and treatment strategies for ccRCC. In addition to examining how miRNA axes regulate the TME and highlighting their potential as novel biomarkers and therapeutic targets for RCC, this study attempts to give a summary of current developments regarding the involvement of the miRNA axis in RCC pathogenesis.

miRNAs are tiny RNA molecules that are present in many different animals and have a length of about 23 nucleotides. They work as antisense transcripts, which lower post-transcriptional levels of their target genes' expression. A single miRNA may have a little regulatory impact on its target gene, but the network of interactions between miRNAs, their target genes, and downstream effectors is crucial for controlling cellular processes [10]. After undergoing multiple processing stages to create precursor and mature miRNAs, the majority of miRNAs are transcribed from DNA templates into main miRNAs. Drosha and Dicer are two RNase III enzymes that process miRNA in the cytoplasm and nucleus compartments, respectively [11].
The fact that a single gene is usually regulated by numerous miRNAs and that each miRNA can target multiple genes with sequences complementary to its seed region further emphasizes the crucial role that miRNAs play in gene regulation [12]. An estimated one-third of the human genome is thought to be regulated by miRNAs, which also affect almost all important cellular functions [13]. The involvement of miRNAs in cancer pathogenesis has been extensively studied [14]. These molecules have been shown to impact essential aspects of cancer biology, including sustained cell proliferation, evasion of growth-inhibitory signals, and promotion of angiogenesis [15].
When miR-15a and miR-16-1 were discovered in a commonly deleted region in B-cell chronic lymphocytic leukemia, the significance of miRNAs in cancer was first brought to light [16]. Later studies found more genetic changes in miRNA-coding genes in a number of malignancies, such as breast cancer [17], ovarian cancer, lung cancer [18], and melanoma. Additionally, it has been demonstrated that oncogenes like c-Myc decrease tumor-suppressor miRNAs while modulating the expression of oncogenic miRNAs [19]. To learn more about the function miRNA expression profiles play in the pathophysiology of RCC, a number of studies have determined these profiles in a variety of biological samples [20].

Numerous investigations have looked at how miRNAs and their target genes are expressed differently in RCC samples than in healthy controls. Li et al., for instance, found that 473 genes were upregulated and 521 genes were downregulated in RCC samples. RHCG, RALYL, SLC4A1, UMOD, and CA9 were identified as important nodes with high interaction degrees in the protein-protein interaction network analysis. The cytokine and cytokine receptor signaling pathway was found to be enriched in the genes that were differentially expressed [21]. These methods are useful for locating possible RCC biomarkers and treatment targets. Furthermore, other miRNAs have been shown to be dysregulated in RCC samples by other studies. Figure 1 shows how the PTEN tumor suppressor interacts with a number of dysregulated miRNAs in RCC.

In RCC, several oncomiRs have been found. Gottardo et al. found that tissue samples from RCC patients had higher levels of let-7f-2, miR-28, miR-185, and miR-27 than normal kidney tissue. It's interesting to note that these miRNAs were different from those that were increased in samples of bladder cancer from the same patient group, indicating that these two urogenital malignancies had different miRNA signatures [22]. Wulfken et al. observed the expression of miRNA in RCC patients' tissue and serum samples. 36 of the 109 circulating miRNAs that they found to be overexpressed in cancer patients were also increased in tissue samples. An additional cohort of RCC patients had miR-1233 elevated, according to further validation; individuals with angiomyolipoma or oncocytoma showed similar expression patterns [23].
Another notable oncomiR, miR-301a, is upregulated in RCC cell lines and clinical samples. Its overexpression has been linked to advanced tumor stages and poor patient survival. Mechanistically, miR-301a directly targets the PTEN tumor suppressor [24]. Similarly, miR-22 and miR-193a-3p have also been shown to suppress PTEN expression in RCC cells [25]. Additionally, miR-1293 is upregulated in RCC cells, promoting their viability, migration, and invasiveness by inhibiting Hydrocyanic Oxidase 2 [26]. Table 1 summarizes the roles of upregulated miRNAs in RCC.

RAS/MAPK signaling pathway

Numerous studies have shown that the Ras-Raf-MEK-ERK signaling pathway is essential to the initiation and spread of cancer [27]. For instance, RCC cells overexpress astrocyte-elevated gene-1 (AEG-1), a downstream gene of Ha-ras, which encourages cell invasion and proliferation. Interestingly, it has been demonstrated that miR-384 reverses these effects by specifically targeting AEG-1 [28]. According to another study, RCC has an increased level of p21-activated kinase 5 (PAK5), which reduces the metastasis-suppressive effects of miR-106a-5p [29]. Rho-associated protein kinase 1 (ROCK1) and Kirsten rat sarcoma viral oncogene (KRAS), are also highly expressed in RCC cells and aid in the growth of tumors. Accordingly, miR-199a and miR-532-5p can lessen these effects. Furthermore, it has been demonstrated that miR-532-5p suppresses P-ERK and ETS1 expression in vivo and inhibits tumor growth. In many types of cancer, ETS1 acts as an oncogene [30].
In RCC, miR-622/200b decreases phosphorylated ERK (P-ERK), a crucial element of the MAPK signaling pathway, while CCL18/LAMA4 increases it. MiR-622 can reverse the tumor progression caused by elevated CCL18 and LAMA4 expression in kidney carcinoma. Laminin subunit alpha-4 (LAMA4) and C-C motif chemokine 18 (CCL18) are both essential for the growth of tumors [31]. Furthermore, it has been observed that overexpression of miR-363 inhibits tumor growth in ccRCC [32]. Similarly, in RCC, spindle and kinetochore-associated protein 1 (SKA1) stimulates tumor growth, increases P-ERK1/2 and P-AKT levels. However, miR-10a-5p has the ability to reverse these effects. Numerous malignancies have been found to have SKA1 as an oncogene [33].

PI3K/AKT/mTOR signaling pathway

Renal cancer frequently exhibits dysregulation of the PI3K/Akt/mTOR signaling pathway [34]. This pathway's downstream target, Forkhead box protein M1 (FOXM1), is a member of the Forkhead box family and is highly expressed in RCC, which accelerates the growth of tumors. Notably, miR-149 and miR-320a can reverse these carcinogenic effects [35]. In RCC, oncogenes such as KIFC1, eIF4E, and HMGN5 upregulate the expression of PI3K and Akt, whereas miR-338-3p, miR-15a, and miR-488 can downregulate it. The advancement of renal carcinoma caused by these oncogenes is inhibited by overexpression of miR-338-3p, miR-15a, and miR-488 [36].
In RCC, SPOP can decrease PTEN expression, a crucial regulator of the PI3K/Akt pathway, whereas miR-520/372/373 and miR-203 can increase it. Through its targeting of SPOP, miR-520/372/373 overexpression inhibits the growth of tumors [37]. The tumor-suppressive effects of miR-148a are also reversed by AKT2, a member of the Akt family that is overexpressed in RCC. Via Rab14, a GTPase in the RAS oncogene family, miR-148a stimulates the production of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and makes RCC cells more sensitive to cisplatin by lowering P-Akt and mTOR levels [38].
Additionally, splicing factor 2 (SF2) increases the expression of P-Akt and P-ERK in RCC, while miR-766-3p reduces their levels. Overexpression of miR-766-3p suppresses tumor growth by targeting SF2, a known promoter of carcinogenesis [39]. Another critical component of the Akt pathway, PDK1  is overexpressed in RCC, driving cell proliferation, but its effects are reversed by miR-375 [40]. Remarkably, miR-100 has been demonstrated to raise LC3 and LC3-II/LC3-I levels while downregulating mTOR and NOX4 expression. These modifications improve autophagy and lessen the aggression of RCC cells [41]. The connections between these compounds and their regulatory miRNAs are depicted in a Figure 2.

VEGF signaling pathway

Vascular endothelial growth factor (VEGF) is integral to tumor progression and angiogenesis [42]. In RCC, VEGFA is overexpressed and significantly promotes tumor growth and metastasis. However, its effects can be counteracted by miR-205-5p and miR-299-3p. miR-205-5p enhances RCC cells' sensitivity to treatments such as sunitinib, paclitaxel, 5-FU, and oxaliplatin by suppressing VEGFA expression [43]. Similarly, the growth hormone receptor (GHR) upregulates VEGF, thereby increasing the mobility of RCC cells, while this effect is reversed by miR-363. Additionally, GHR has been shown to positively correlate with RCC proliferation [44].
Another important miRNA, miR-218, has been shown to reduce tumor angiogenesis and decrease the migration of human umbilical vein endothelial cells (HUVECs) by suppressing VEGFA production and blocking the p-PI3K/p-Akt/p-mTOR signaling pathway. The downregulation of GRB2-associated binding protein 2 (GAB2), a crucial oncogene linked to several malignancies, mediates these effects [45]. Additionally, there is evidence that VEGF and fibroblast growth factor (FGF) play similar functions in the migration and activation of angioblasts during vascular development [46]. For example, FGF2 promotes invasion and tube formation in HUVECs within RCC. However, miR-148b-3p can counteract these pro-angiogenic effects by downregulating platelet-derived growth factor-BB/D (PDGF-BB/D), VEGFA, and FGF2 activity. In a number of malignancies, PDGF-BB and PDGF-D are recognized to act as strong pro-angiogenic mediators [47].

Metabolism/Immunity-related mechanism

Metabolic alterations within the TME contribute to immune evasion by generating immunosuppressive metabolites [48]. For example, overexpression of PLP2 in clear cell RCC (ccRCC) promotes tumor growth and mobility, enhances VEGFA expression, and facilitates lipid accumulation, an effect that can be counteracted by miR-765. PLP2, a newly identified gene upregulated in cancer, has been associated with oncogenic activity in breast cancer [49]. Studies have shown that RCC cells, like many other cancer forms, depend on aerobic glycolysis to produce ATP and have aberrant HIF stabilization [50]. In particular, ccRCC cells with high PDK1 expression increase the extracellular acidification rate (ECAR) in hypoxic environments, which boosts ATP synthesis and lowers the oxygen consumption rate (OCR) of tumor cells. MiR-409-3p can correct these metabolic alterations [51].
One of the key areas of research continues to be tumor immune evasion, which is a characteristic of cancer. MiR-497-5p can counteract the effect of overexpression of PD-L1, the ligand for the immunological checkpoint receptor PD-1, which promotes tumor growth in RCC [52]. Tumor formation is also influenced by TLRs, which control the innate immune feedback. For example, miR-216a targets TLR4 to inhibit RCC growth in vitro and in vivo [53].

mTOR/Metabolic pathway

In many forms of cancer, the protein kinase mTOR is essential for controlling cell division and metabolism [54]. miR-92b-3p activates the mTOR signaling pathway and accelerates the development of ccRCC by decreasing the expression of TSC complex subunit 1 (TSC1) and increasing the phosphorylation of p70S6 kinase, a downstream target of TSC1. The role of TSC1 is to inhibit mTORC1 [55]. According to a different study, overexpression of miR-501-5p activates p-mTOR, which causes cell autophagy and p53 degradation in renal cancer, which aids in the tumor's growth in RCC [56]. Recent studies further reveal that IMPA2 (inositol monophosphatase 2) might reduce p-mTORC1 levels in ccRCC cells, establishing it as a possible biomarker for directing the use of mTOR inhibitors in treating metastatic ccRCC in clinical settings [57]. Furthermore, reduced expression of IMPA2 in ccRCC leads to decreased levels of N-cadherin and Slug, hindering tumor metastasis by downregulating miR-25-3p [58]. Altered cellular energetics is a characteristic of RCC and many other malignancies. For example, the pentose phosphate pathway (PPP) is typically increased in RCC cells, and G6PD, a major enzyme in this system, is a rate-limiting component. G6PD inhibition reduces the survival of RCC cells [59].

PI3K/AKT signaling pathway

One of the main characteristics of carcinogenesis in RCC is the high level of activation and frequent mutations in the PI3K/Akt signaling pathway [60]. In RCC, ST3GalIV downregulates p-PI3K and p-Akt expression, whereas miR-193a-3p and miR-224 upregulate them. Both miR-193a-3p and miR-224 target ST3GalIV (alpha-2,3-sialyltransferase IV), which aids in the growth of tumors. The production of α-2,3-sialic acid on cell surfaces, which is catalyzed by ST3GalIV, is intimately associated with the capacity for malignancies to spread [61]. Another study revealed that FRK (Fyn-related kinase) enhances p-PTEN levels, as FRK acts as a substrate for PTEN, although this effect is inhibited by miR-19 in ccRCC. Moreover, overexpression of miR-19 promotes cell proliferation in renal cancer by modulating FRK and PTEN [62]. FOXO3, a downstream target of the PI3K-Akt pathway is negatively regulated by miR-122 and highly expressed in ccRCC. In kidney cancer, miR-122 overexpression increases E-cadherin expression and stimulates tumor growth [63]. It's interesting to note that BTG3 (B-cell translocation gene 3) suppresses prostate cancer cells by lowering p-Akt levels [64]. By adversely controlling miR-142-5p, BTG3 inhibits cell growth in RCC [65] (Figure 3).

TGF-b/Wnt signaling pathway

Numerous developmental processes are regulated by TGF-β and Wnt signaling pathways, which are also linked to the development of some malignancies [66]. SMAD family member 4 (SMAD4), for example, is an essential part of the TGF-β pathway. In vitro, RCC tumor metastasis is inhibited by decreased SMAD4 expression; however, miR-452-5p can reverse this effect. Furthermore, miR-452-5p targets SMAD4 to decrease kidney cancer cells' susceptibility to tyrosine kinase inhibitors (TKIs) [67]. A member of the TGF-β superfamily, BMPR1B (bone morphogenetic protein receptor type 1B) has a role in the emergence of certain types of cancer [68]. Similarly, miR-1274a downregulates BMPR1B to increase ccRCC cell proliferation and decrease apoptosis [69]. Dickkopf1 (DKK1) and DKK3, both extracellular Wnt pathway inhibitors, have been demonstrated in earlier research to function as tumor suppressors in renal carcinoma [70]. Similarly, in RCC, miR-543 and miR-125b promote tumor growth by inhibiting DKK1 and DKK3, respectively. Additionally, renal cancer cells are less sensitive to chemotherapeutic medications like doxorubicin and sunitinib when miR-125b is overexpressed [71] (Figure 3).

NF-kB signaling pathway

In renal cancer, miR-146b-5p lowers the protein levels of TRAF6 (TNF receptor-associated factor 6) and NF-κB (p65). Additionally, miR-146b-5p enhances tumor growth by reducing serum IFN-γ levels and altering TRAF6. In the NF-κB pathway, TRAF6 functions as a signal transducer, and IFN-γ has been utilized to treat ovarian cancer [72]. It's interesting to note that KLF6 has been demonstrated to suppress the growth of glioblastoma by reducing the localization of p65 [73]. Similarly, in ccRCC, overexpression of KLF6 reduces tumor development and raises p21 levels. However, p21 has been demonstrated to deactivate the NF-κB pathway in prostate cancer, and miR-543 can restore this impact [74]. According to earlier research, TNF deactivates the NF-κB pathway, which results in both necroptosis and apoptosis [75]. In contrast, miR-381-3p has no discernible effect on TNF-induced NF-κB activation but suppresses TNF-induced apoptosis and necroptosis in renal cancer. This encourages tumor growth and points to a dismal prognosis for pRCC patients. These results suggest that different cell types may have distinct functions for the NF-κB pathway. A key regulatory protein in planned cell necroptosis is RIPK3 [76] (Figure 3).

Recent research has identified several novel deregulated miRNAs that are specific to different RCC subtypes, and these miRNAs can effectively distinguish ccRCC from normal kidney tissue [77]. By controlling the EphA2/p-FAK/p-AKT/MMPs signaling cascade, miR-141 functions as a major inhibitor of ccRCC cell growth and metastasis, making it a promising biomarker for differentiating ccRCC from normal tissues [78]. Another study showed that the miRNA profiles of malignant and non-malignant tissues could be easily distinguished from one another, with samples classified with a 97% accuracy rate using a combination of miR-141 and miR-155 [79]. Additionally, RCC was correctly distinguished from normal kidney tissue, oncocytoma from RCC, and chRCC from oncocytoma using a panel that included miR-141 and miR-200b [80]. Furthermore, Faragalla et al. revealed that miR-21 expression had an 83% sensitivity and 90% specificity in differentiating ccRCC and pRCC from chRCC and oncocytoma [79]. Youssef et al. developed a classification system that distinguishes between different RCC subtypes in as few as four steps using distinct miRNA signatures. This technique showed 100% accuracy in differentiating oncocytoma from chRCC, 97% sensitivity in differentiating normal tissue from RCC, 100% sensitivity in differentiating ccRCC, and 97% sensitivity in differentiating pRCC [81].
Extracellular miRNAs, including those in serum or urine, have become interesting biomarkers for RCC diagnosis and prognosis since they are likewise dysregulated in RCC patients. For example, it was possible to distinguish RCC from healthy controls by observing that serum miR-378 levels were higher and miR-451 levels were lower in RCC patients. With an AUC of 0.86 and a sensitivity of 81% and specificity of 83%, the combination of these two miRNAs enhanced stratification [82]. Patients with RCC had elevated serum levels of miR-1233, which demonstrated a sensitivity of 77.4% and specificity of 37.6%. One possible biomarker for RCC has been shown to be miR-1233 [83]. Furthermore, blood levels of miR-210 were considerably greater in ccRCC patients than in healthy controls, indicating that miR-210 was elevated in the early stages of the disease. For diagnostic purposes, this miRNA showed 81.0% sensitivity and 79.4% specificity [84, 85]. While miR-15a was nearly undetectable in oncocytoma, other tumors, and urinary tract inflammation, it was found to be elevated in RCC patients' urine samples [86]. Given their excellent diagnostic accuracy in RCC patients, miRNAs may be used as next-generation disease detection biomarkers. To confirm these findings and establish their regular clinical use, however, extensive research and additional developments are required [87].

Short, non-coding RNAs known as miRNAs are evolutionarily conserved and control gene expression by directly destroying or preventing mRNA translation. There is mounting evidence that miRNAs which can originate from either the guide strands, the passenger strands, or both are essential for the development of cancer. Our results further demonstrate the important role that miRNAs play in cancer, where they serve as oncomiRs, prognostic indicators, prospective therapeutic targets, and biomarkers for detection. They have especially interesting promise as therapeutic targets for RCC and as biomarkers in liquid biopsies. Although lncRNAs and circular RNAs have received the majority of current attention in the field of non-coding RNA, studies have also looked into targeting miRNAs or employing miRNA sponges to study their roles. In fact, research on miRNA remains an important field of study for cancer and other illnesses. Additionally, scientists have created novel materials and small molecule drugs that have anticancer properties in vivo by modulating miRNA levels. The findings of the RNA therapy and liquid biopsy-based diagnostics clinical trials that are just beginning are anticipated to have a big influence on how kidney cancer is treated in the years to come.

Acknowledgements

None.

Ethical policy

Non applicable.

Availability of data and materials

All data generated or analysed during this study are included in this publication.

Author contributions

DCA searched academic literature, wrote the draft manuscript and draw the figures; SBM supervised the review writting progress and approved the final manuscript submission.

Competing interests

None.

Funding

None.

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