Differential expression and functions of miRNAs in bladder cancer
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Hao Huang
Abstract
Bladder cancer (BC), a urologic disease, commonly occurs globally and is very invasive. Patients with invasive BC have low 5-year survival rate. Hence, the mechanisms underlying BC development and progression should be elucidated. MicroRNAs (miRNAs), as common noncoding RNAs, are receiving increasing attention because of their biological functions. The irregular expression patterns of miRNAs are linked to BC occurrence; therefore, determining the functions of miRNAs in abnormally expressed BC tissues might enable to elucidate the pathogenetic mechanism of BC and offer new markers for the prognosis, diagnosis, and therapy of BC. Here, we consolidate the primary roles of miRNAs with atypical expression in BC development as well as their association with BC pathological grades and chemotherapy resistance development in patients with BC.
Introduction
As a malignant cancer of the urinary tract, bladder cancer (BC) ranks fifth among the commonly occurring cancers globally; moreover, it has a high incidence of morbidity and mortality [1]. A previous study on the association of cancer mortality with gender revealed that male and female patients with BC show a difference in the mortality rate, with higher mortality in male patients than in female patients [2]. BC incidence is increasing every year [3]. According to infiltration depth, there are two classes of BC: NMIBC, non-muscle-invasive bladder cancer; MIBC, muscle-invasive bladder cancer [4]. MIBC has a higher mortality rate [5], and following radical resection, patients with BC have a 5-year survival rate of only 50% [6].
Several chemotherapeutic regimens have exhibited limited efficacy in clinical trials for treating advanced BC. This has necessitated the search for novel prognostic markers together with more efficacious therapeutic approaches. MicroRNAs (miRNAs) are associated with the formation of several cancers, including BC [7, 8]. Hence, studying BC-related miRNAs will enable to clarify which molecular mechanisms are responsible for BC’s occurrence, progression, and metastasis and contribute to develop a powerful approach to screen potential biomarkers to classify, diagnose, prognose, and treat BC.
miRNAs were first discovered in 1993 in mammals [9]. They are 19- to 24-nucleotide long endogenous noncoding RNAs that participate in regulating target genes after transcription [10], [11], [12], [13]. miRNAs were recognized to be relevant after they were found to be involved in developing chronic lymphocytic carcinoma [14]. Thus far, 38,589 miRNAs have been identified in 271 species, and these miRNAs have evolved across species [15]. The gene maps of miRNAs include genomes of approximately 1% of different species, wherein each genome contains numerous target genes; furthermore, miRNAs control the expression of approximately 30% coding genes [16]. According to bioinformatics analysis, 30–60% of protein-coding genes of the human genome are controlled by miRNAs [17]. An individual miRNA controls the expression level for >200 genes, while an individual gene is controlled through many miRNA systems [18, 19]. miRNAs contribute to cancer development [20]; they perform crucial functions in tumor cell differentiation, proliferation, and metastasis [21].
miRNAs dysregulation in BC
The miRNA expression in tumor tissues is altered at different levels when compared with that in normal tissues; many malignancies such as BC show aberrant expression of miRNAs. Therefore, novel methods have been applied to evaluate miRNA expression [11, 13]. Differential miRNA expression in normal and tumor cells indicates that the atypical expression miRNAs leads to cancer development [20]. miRNA dysregulation may be caused by multiple mechanisms, which include genetic alterations, epigenetic changes, and single nucleotide polymorphisms in genes encoding miRNAs or defects in factors regulating miRNA biogenesis [22]. A previous study showed that BC development is related to the upregulation or downregulation of miRNA expression [23]. As shown in Figure 1, upregulated miRNAs suppress antioncogene expression, whereas downregulated miRNAs can negatively regulate oncogene expression [23], [24], [25]. Expression profiling of miRNAs involved in BC revealed that miR-183 and miR-182 are frequently upregulated [26], [27], [28], [29], [30]; miR-125b, miR-145, and miR-143 are the commonly downregulated miRNAs [26], [27], [28, 30], [31], [32].
Effects of dysregulated expression of miRNAs on bladder cancer progression. KIF18B, kinesin family member 18B; RECK, reversion-inducing cysteine-rich protein with Kazal motifs; IGF-1R, insulin-like growth factor type 1 receptor; IRS1, insulin receptor substrate 1; PI3K, phosphatidylinositol 3-kinase; PDK1, 3-phosphoinositide-dependent kinase 1; Akt, AKT kinase-transforming protein; PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; P, phosphorylated; PTEN, phosphatase & tensin homolog.
Upregulated miRNAs may participate in BC progression. Some upregulated miRNAs, for example, miR-556-3p, miR-940, and miR-130b-3p, enhance the ability of tumor cells to migrate, proliferate, and invade [33]. Furthermore, miRNAs like miR-940 and miR-182-5p, which are upregulated, show antiapoptotic effects on BC cells, while miR-221 exerts its effects on cell apoptosis by affecting TNF-related apoptosis-inducing ligand and inhibiting caspase-3; these miRNAs also promote BC [34]. By using microarray technology, Braicu et al. [35] compared noncancerous and BC tissues; the authors showed that 187 miRNAs were upregulated, including miR-141b, miR-200s, and miR-205. They validated their findings through quantitative polymerase chain reaction (qPCR). The relationship of these upregulated miRNAs with BC development provides a new way to investigate the markers to diagnose and prognose BC.
Downregulated miRNAs might induce tumor suppression in BC, and almost all downregulated miRNAs suppress the angiogenesis, proliferation of cells, migration of cells, and cell cycle arrest induction in BC cells [36]. Several studies have assessed the downregulation of miRNAs in BC have been investigated by many studies. According to Zaravinos et al. [37], expression levels of miR-10b, miR-145, miR-126, miR-296-5p, miR221, miR-19a, and miR-378 were downregulated in BC cells in comparison to those in the adjacent normal uroepithelium. Zhang et al. [38] detected that in BC cells, miR-139-3 expression was significantly downregulated; additionally, miR-13-3p/KIF18B/Wnt/β-linked proteins remarkably prevented BC progression of BC. Liao et al. [39] reported downregulated miR-539 expression in BC tissues and cells in comparison to that in the normal bladder epithelial cell line as well as matched adjacent normal bladder tissues; they also showed that miR-539 possibly functions as a BC suppressor. Another team developed a survival estimation method called Bladder Cancer Survival and showed downregulated miR-129 expression in BC tissues; they also reported that miR-129 acts a good prognosis biomarker [40]. Moreover, miR-26a, miR-143, miR-195, miR-145, miR-1, and miR-133a/b showed downregulation of their expression in BC tissues in comparison to those in normal bladder tissues; thus, this finding indicated tumor suppressive roles of these miRNAs [24]. A commonly downregulated miRNA is miR-145 in BC, and it markedly inhibits the ability of BC cells to invade, migrate, and proliferate [24, 41]. Determining downregulated miRNAs in BC can yield novel strategies to treat BC; furthermore, it is anticipated that additional studies in the future will investigate the feasibility of using such miRNAs.
Zhang et al. [38] detected a marked reduction in miR-139-3p expression in BC; moreover, the upregulation of this miRNA significantly reduced BC cells’ capacity to metastasize, invade, and proliferate and blocked progression from G0 to G1. According to Chen et al., miR-381 expression in BC tissues and cells is downregulated; the authors also revealed that several biological responses such as invasion, proliferation, migration, tumor formation ability, and resistance to apoptosis in BC cells were suppressed following the artificial upregulation of miR-381 expression [42]. These results, which contradict the mainstream results, should be confirmed further. Table 1 lists the functions of dysregulated miRNAs in the cells of BC.
Roles of miRNAs aberrantly expressed in bladder cancer.
| miRNAs | Expression | Major role | miRNAs | Expression | Major role |
|---|---|---|---|---|---|
| miR-21 [43] | Up | Progression of BC | miR-1-3p [44] | Down | Prevents the proliferation, invasion, and migration of BC cells in vitro |
| miR-16-5p [45] | Up | Decreases cell viability as well as increases autophagy and apoptosis | miR-22 [46] | Down | Induces apoptosis and inhibits EMT processes, proliferation, and motility in BC cells in vitro |
| miR-22-3p [47] | Up | Promotes the chemoresistance of BC with NET1 as the target | miR-34a [48] | Down | Decreases the capacity of BC cells to invade and migrate |
| miR-23a-3p [35] | Up | Involved in the composition of the BC oncogenic network | miR-99a-5p [49] | Down | Induces cell senescence of gemcitabine-resistant BC cells by targeting SMARCD1 |
| miR-23a and miR-27a [50] | Up | Promotes the proliferation, migration, invasion, and EMT of BC | miR-106a [51] | Down | Arrests BC cells in the G1 phase and inhibits their migration and invasion |
| miR-30a [52] | Up | Increases the potential of BC cells to metastasize, migrate, and invade | miR-143-5p [35] | Down | Inhibits BC development |
| miR-93-5p [53] | Up | Enhances the proliferation and migration of bladder urothelial carcinoma by inhibiting KLF9 | miR-143 [54] | Down | Inhibits BC cell proliferation and improves the drug sensitivity of BC cells to gemcitabine |
| miR-92b [33] | Up | Promotes the migration, invasion, and EMT of BC cells | miR-145 [55] | Down | Involved in the downregulation of some markers of stemness |
| miR-96 [56] | Up | Promotes EMT in BC cells | miR-148a-3p [57] | Down | Induces BC cell apoptosis via controlling Bcl-2 expression |
| miR-130b-3p [33] | Up | Increases the invasion, migration, and cytoskeleton rearrangement | miR-154 [58] | Down | Inhibits BC cells’ proliferation, migration, and invasion |
| miR-141-3p [35] | Up | Enhances the capacity of BC cells to develop, invade, and metastasize | miR-155-5p, miR-330-5p [59] | Down | Prevent angiogenesis, migration, and invasion of BC cells |
| miR-138-5p [60] | Up | Could perform a vital role in controlling TERT expression and immune checkpoint ligand expression | miR-183-5p [61] | Down | miR-183-5p-PNPT axis controls BC cell apoptosis and could be used as a therapy for BC |
| miR143/145 [62] | Up | Associated with BC invasiveness and poor prognosis | miR-192 [63] | Down | Its expression in BC patients’ urine sediment is associated with tumor progression |
| miR-146b [64] | Up | Promotes invasive and nonanchored growth of BC cells | miR-193b [65] | Down | Downregulates proto-oncogene expression and blocks cell cycle, cell invasion, and migration of BC cells |
| miR-146a-5p [66] | Up | Performs a carcinogenic function and is positively linked with the recurrence and with poor prognosis in BC patients | miR-203 [67] | Down | Predicts progression-free survival and prognosis of BC patients on cisplatin-based chemotherapy |
| miR-155 [68] | Up | Promotes tumor formation in BC and enhances in vitro proliferation and in vivo tumorigenesis | miR-214 [67] | Down | Urinary free cell miR-214 can function as a prognostic biomarker for enabling tumor stratification and early diagnosis in BC patients |
| miR-182-5p [69] | Up | Enables human BC cells to proliferate and migrate via the FOXF2/SHH axis | miR-214 [70] | Down | Inhibits BC cell oncogenicity in vitro |
| miR-193a-3p [71] | Up | Promotes multidrug resistance in BC by inhibiting LOXL4 expression | miR-218 [55] | Down | Sensitizes BC cells to cisplatin chemotherapy through Glut1 targeting |
| miR-193a-3p [72] | Up | Regulates chemoresistance to multiple drugs in BC by activating DNA damage response pathways and increases BC cell chemoresistance by activating the ING5 gene | miR-330 [73] | Down | Its expression can be counteracted by the depletion of circFARSA, thereby inhibiting BC cell proliferation and migration |
| miR-196a-5p [74] | Up | Induces the inhibition of cisplatin/gemcitabine-induced apoptosis by targeting p27Kip1 involved in UCA1 | miR-323a-3p [75] | Down | Inhibits the capability of BC cells to invade and migrate by regulating EMT progression in BC |
| miR-200 family (miR-200a, miR-200b, and miR-429, miR-200c and miR-141) [76] | Up | Family members of miR-200 control EMT process in MIBC via ZEB1 and ZEB2 | miR-370-3p [77] | Down | Negative control of cell invasion of UBC by inhibiting Wnt7a |
| miR-205-5p [35] | Up | Regulates BC cell growth, metastasis, and invasion | miR-378c and miR-30e [78] | Down | Associated with patients’ survival |
| miR-294 [79] | Up | Increases motility and proliferation of BC cells | miR-411 [80] | Down | Reduces BC cell proliferation as well as prompts cell cycle arrest in G2/M |
| miR-301b [81] | Up | Suppresses EGR1 expression to enhance the capacity of BC cells to migrate, invade, and proliferate | miR-433 [82] | Down | miR-433 overexpression prevents BC cells’ colony formation, proliferation, and cell motility and causes EMT |
| miR-340 [83] | Up | Functions as a likely target for treating BC | miR-497-5p [84] | Down | Low miR-497-5p expression and high CEP55 and HMGA2 expression are related to clinical staging as well as pathological grade of more advanced tumors |
| miR-495 [85] | Up | Increases BC cell proliferation and invasion | miR-582-5p [86] | Down | The miR-582-FOXG1 axis might perform a crucial function in cell invasion and act as a key prognostic marker |
| miR-675 [87] | Up | Stimulates cell proliferation and cell cycle of BC cells as well as BC progression, stops cell cycle arrest, as well as suppresses apoptosis by controlling p53 activation | miR-1307-5p [88] | Down | Tumor suppressor in BC |
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miRNAs, micro ribonucleic acids; BC, bladder cancer; NET1, neuroepithelial cell transformation 1; EMT, epithelial–mesenchymal transition; LOXL4, lysyl oxidase-like 4; DNA, deoxyribonucleic acid; ING5, inhibitor of growth 5; p27Kip1, kinase inhibitor proteins 27 Kip1; UCA1, urothelial cancer-associated 1; MIBC, muscle-invasive bladder cancer; ZEB1, zinc finger E-box-binding homeobox 1; ZEB2, zinc finger E-box-binding homeobox 2; Glut1, glucose transporter type 1; UBC, urinary bladder cancer; Wnt7a, wnt protein 7a; EGR1, early growth response gene 1; p53, cellular tumor antigen p53; FOXF2, forkhead box F2; SHH, sonic hedgehog; KLF9, kruppel-like factor 9; circFARSA, circRNA phenylalanyl-tRNA synthetase subunit alpha; FOXG1, forkhead box G1; TERT, telemerase reverse transcriptase; PNPT, polyribonucleotide nucleotidyltransferase 1; CEP55, centrosomal protein 55; HMGA2, high mobility group A2.
miRNAs expressed in BC patients’ body fluids
Early clinical diagnosis of BC allows early intervention in BC patients. Presently, the cytology findings of urine samples are used to diagnose and monitor BC [89]; however, specific biomarkers are yet to be identified. Biomarkers are stable molecules with disease specificity, and they can be easily obtained and assessed. According to a recent study, miRNAs are a new class of cancer biomarkers [90]; moreover, miRNA profiles are more accurate than miRNA classifiers to classify hypofractionated tumors, thus indicating the usefulness of miRNAs for early cancer diagnosis [91]. Body fluids contain miRNAs and miRNAs, and therefore, they are vital to enable early BC diagnosis. Novel biochemical markers to diagnose BC are confirmed based on alterations in miRNA concentrations in the samples of urine and blood [92]. Figure 2 shows the process of detecting miRNAs in body fluid samples.
Detection of microRNAs in the body fluid to determine their roles in bladder cancer. PCR, polymerase chain reaction.
Microarray analysis conducted in a previous study showed miR-663b, miR-505, and miR-363 were upregulated as well as miR-100, miR-194, miR-497, miR-99a, and miR-1 were downregulated in BC patients’ plasma [93]. Luo et al. [94] detected downregulated expression of miRNA-150 in the blood of patients showing early BC; furthermore, the authors also found that miRNA-150 attenuated CASC11 expression, a long-stranded noncoding RNA upregulated in the blood, thereby inhibiting BC cell proliferation. miR-182, miR-199a, and miR-126 are overexpressed in BC patients’ urine, and thus, they are useful to diagnose BC with a high specificity and sensitivity [29, 95]. miR-183 and miR-96 expressional levels are upregulated in BC patients’ urine; these miRNAs are highly accurate to diagnose BC and show a significant correlation with tumor staging and grading [96]. Eissa et al. [97] detected miR-10b, miR-29c, and miR-210 overexpression in BC patients’ urine and reported that these miRNAs have appropriate levels of sensitivity and specificity for BC diagnosis. Moreover, the results’ sensitivity increased by 95.2% following miRNA expression determination and urine cytological analysis. Zhang et al. [98] confirmed that miR-155 was overexpressed in the urine of NMIBC patients and that this overexpression was correlated with tumor grade and stage; furthermore, it was significantly downregulated after transurethral bladder resection. In another study, Wang et al. [99] noted that the miR200 family members showed downregulated expression in BC patients’ urine, and following tumor resection, specific miRNA levels were significantly increased. miR-452, miR-143, and miR-222 present in urine samples can be used in clinical settings for the diagnosis of noninvasive BC [100]. Additionally, miR-200b, miR-182, and miR-9 linked with the invasiveness of BC and patients’ survival [101].
miRNA concentrations in serum show conflicting results because of some variations in the reported data on miRNA expression profiles in blood. miRNAs like miR-106a-5p, miR-374a, miR-942, miR-378, and miR142-3p were upregulated in the blood; however, these findings should be further confirmed by studies with a greater sample size [102]. These alterations in the expression levels of miRNAs in urine and blood indicate that they could considered new biochemical markers for BC diagnosis [92]. These miRNAs could be involved in BC’s diagnosis, prognosis, and treatment, thus deserving additional detailed studies. Table 2 summarizes the miRNAs with dysregulated expression in urine as well as blood of BC patients and the roles of these miRNAs.
Aberrantly expressed miRNAs in BC patients’ urine and blood samples and their roles.
| miRNA | Expression in urine | Major role | Expression in blood | Major role | References |
|---|---|---|---|---|---|
| miR-1 | Down | Provides a basis for molecular diagnosis | Down | Early diagnosis | [93, 103] |
| miR-15b | Down | Early diagnosis | Down | Early diagnosis | [104, 105] |
| miR-21 | Up | Early diagnosis | Up | Prognostic and therapeutic marker for BC | [106, 107] |
| miR-25 | Up | Noninvasive diagnosis | Down | Noninvasive diagnosis | [108, 109] |
| miR-27a | Down | Noninvasive diagnosis | Down | Associated with MIBC prediction and prognosis | [108, 110] |
| miR-92a | Up | Noninvasive diagnosis | Down | Early diagnosis | [108, 111] |
| miR-99a | Down | Noninvasive diagnosis | Down | Early diagnosis | [93, 103] |
| miR-100 | Down | Early diagnosis | Down | Early diagnosis | [104, 111] |
| miR-142-3p | Down | Noninvasive diagnosis | Up | Serves as a diagnostic basis | [102, 108] |
| miR-143 | Down | Noninvasive diagnosis | Down | Early diagnosis | [108, 111] |
| miR-146a-5p | Up | Noninvasive diagnosis and a therapeutic target | Down | Associated with MIBC diagnosis and prognosis | [110, 112] |
| miR-152 | Down | Related to the development of BC | Up | Associated with the recurrence of NMIBC | [105, 113] |
| miR-192 | Down | Provides a basis for developing noninvasive markers | Up | Provides a basis for developing noninvasive markers | [107, 114] |
| miR-200b | Down | Provides a basis for developing noninvasive markers | Up | Provides a theoretical basis for diagnosing MIBC | [109, 114] |
| miR-210 | Up | Serves as a marker for BC diagnosis | Up | Useful to screen, predict, and monitor BC development | [97, 115] |
| miR-342-3p | Down | Provides a basis for developing noninvasive markers | Up | Provides a basis for developing noninvasive markers | [107] |
| miR-183-5p | Up | Related to the staging and grading of BC and can be used as a potential tumor marker | Up | Useful biomarker for stable BC diagnosis | [96, 116] |
| miR-203 | Up | Provides a basis for noninvasive diagnosis | Up | Provides a basis for noninvasive diagnosis | [117] |
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miRNAs, micro ribonucleic acids; NMIBC, non-muscle-invasive bladder cancer; BC, bladder cancer; MIBC, muscle-invasive bladder cancer.
miRNAs associated with pathological typing of BC
Histologically, more than 95% of BC originates from the uroepithelium, and these cancers can be categorized into different types; among these different types, stage Ta and T1 cancers confined to the mucosa and submucosa, respectively, are NMIBC, and cancers in stage T2–T4 are MIBC [118]. These different types of cancers show varying clinical presentation. NMIBC constitute approximately 75% of total BC cases, and it has a high recurrence rate [4]; among these BC cases, Ta and T1 stage tumors differ in disease behavior, aggressiveness, and prognosis [119]. The remaining approximately 25% of BCs are MIBC, and among these BC cases, 7% show metastasis at actual diagnosis, thus making MIBC the primary inducer of death in patients with BC [4].
miR-205 can differentiate high-grade and low-grade papillary uroepithelial carcinomas, while miR-145 can differentiate high-grade papillary uroepithelial cancer from invasive cancers [13]. Furthermore, miR-199B-5p expression was found to be almost exclusively associated with NMIBC [120]. According to some studies, miR-10a-5p expression downregulation affects Ta tumor progression, thus suggesting that miR-10a-5p is probably a critical biomarker for the prognosis of this group of patients [121,122]. The expression of miR-200c showed a remarkable association with disease progression among patients with T1 tumors; furthermore, in 100 patients having stage T1 BC in a previous study, those with downregulated miR-200c expression showed more likelihood to exhibit progression to MIBC [123]. qRT-PCR revealed upregulation of miR-143 and miR-222 expression levels in BC tissue samples, which was related to tumor progression and recurrence [101]. Catto et al. [124] analyzed 52 BC samples as well as 20 samples of normal bladder tissue; they detected abnormal expression of miRNAs based on clinicopathological results. The authors also found that downregulation of the expression levels of many miRNAs linked to high-grade BC was related to low-grade BC and their upregulated expression was related to high-grade BC. More, multivariate Cox regression analysis adjusted for staging as well as grading showed that miR-129, miR-518c-5p, miR-133b, and miR-29c exhibited a significant association with disease progression [31]. Another study on 166 NMIBC cases and 80 MIBC cases identified specific features of 15 miRNAs which distinguished between normal and tumor phenotypes [125]. Other specific characteristics such as overexpression of miR-373 and miR-21 were observed in high-grade MIBC targeting the p53 pathway or EMT (epithelial–mesenchymal transition) as compared to that in the normal tissue [126].
Even though few miRNAs might show potential as prognostic markers, the results are debatable, with no standardization of quantification of miRNA expression across all studies. Therefore, further studies should investigate whether miRNAs could be clinically used as prognostic markers for BC. Figure 3 shows miRNA functions involved in diagnosing and treating BC.
Determination of miRNA expression in bladder cancer tissues to diagnose and prognose bladder cancer. qRT-PCR, quantitative real-time polymerase chain reaction.
Role of miRNAs in chemotherapy for drug-resistant BC
Approximately 30% of BC patients show tumor invasion into the urinary muscle tissue and undergo partial or total cystectomy treatment [127]. Post cystectomy, most patients have a poor prognosis after progression to tumor metastasis. The primary chemotherapy regimens for metastatic or locally advanced disease are gemcitabine and cisplatin (GC) as well as methotrexate, vincristine, doxorubicin, and cisplatin (MVAC) [4]. Clinical response rates for these regimens, however, do not exceed 50%, and subsequent chemotherapy and immunotherapy regimens produce secondary resistance that worsens the prognosis of the disease, leading to poor progression-free survival of patients for 3–4 months [128], [129], [130], [131]. Although several chemotherapeutic agents are found to be suitable for platinum-resistant patients, no standard regimen is available for the second-line therapy of MIBC [132]. Based on the European guidelines published in 2020, periflunomide is the sole chemotherapeutic agent approved as the second-line therapy for MIBC [6, 133]. The US FDA approved programmed cell death protein 1 (PD-1)/PD-1 ligand 1 checkpoint inhibitors such as pembrolizumab and nivomab as the second-line immunotherapy because of their identical efficacy and safety in phase III trials [6, 133, 134]. However, the median rate of overall survival was not significantly improved in patients on pembrolizumab or second-line chemotherapy [135]. The various biological functions in BC reflect the miRNA-driven posttranscriptional regulation of mRNAs, including the control of various hallmarks of cancer such as onset, progression, metastasis, and treatment resistance [136, 137]. Thus, miRNAs are interesting candidate prognostic biomarkers for diagnosing BC, and because they control gene expression in tumorigenesis, they could be considered potential candidates for BC therapy [95, 137].
According to accumulating evidence, miRNAs can regulate intracellular signaling pathways in chemotherapy-resistant BC. Based on the microarray analysis of parental cells and cells resistant to gemcitabine, 66 miRNAs with differentially expression were identified in the miRBase database, including 25 unknown human miRPlus sequences as well as 41 miRNAs [138]. Of these miRNAs with differentially expression, two miRNAs, namely miR-138 and miR-1290, were most abundant in cell resistant to gemcitabine [138, 139]. As reported by several studies, the upregulated miR-98, miR-93, and miR-22-3p expression levels showed a positive correlation with chemoresistance in post-targeting mechanisms; this reduced chemotherapeutic efficacy through the stimulation of downstream adaptive mechanisms [47, 140, 141]. miR-98 and miR-93 promote chemoresistance by inhibiting LASS2 upregulation in the mitochondria, thereby affecting mitochondrial functions [141]; moreover, miR-223p targets neuroepithelial cell transformation 1 and mediates extracellular signaling, thus inhibiting chemotherapy-induced cell death [47]. miRNAs determine the drug resistance phenotype of BC cells, especially for multidrug resistance; thus, miRNAs can be considered targets for BC treatment. Drug resistance remains a clinically important hindrance leading to tumor recurrence and metastasis that underlines the importance of this function of miRNAs; this makes miRNAs promising candidates for developing effective therapeutic strategies [142]. Mechanistically, several studies have investigated the mechanism by which miRNAs regulate signaling pathways in BC to affect chemotherapeutic drug resistance, including signaling pathways related to apoptosis, cell cycle, and EMT. Figure 4 shows the relationship between relevant miRNAs and chemoresistance of BCs.
MicroRNAs associated with chemotherapy resistance in BC. Bcl-w, B-cell lymphoma w; PTEN, phosphatase & tensin homolog; PIP3, phosphatidylinositol-3,4,5-kinase; Akt, AKT kinase-transforming protein; mTOR, mammalian target of rapamycin; SIRT-1, NAD-dependent histone deacetylase sirtuin-1; P27, cellular tumor antigen p27; CDK2, cyclin-dependent kinase 2; E2F, E2F transcription factor; P, phosphorylated; CDK4/6, cyclin-dependent kinase 4/6, EMT, epithelial-mesenchymal transition; ZEB1, zinc finger E-box binding homeobox 1; ZEB2, zinc finger E-box binding homeobox 2; Twist1, Twist-related protein 1; MAPK, mitogen-activated protein kinase.
miRNA-mediated apoptosis regulation in BC cells
Apoptosis, a programmed cell death mode, occurs periodically to ensure homeostasis between cell production rate and cell death rate [143]. miRNAs play a crucial part in apoptosis. Dong et al. [144] revealed that LINC00511 targeted miR-143-3p for controlling the migration, apoptosis, and proliferation of BC TCCSUP or SW780 cells, eventually promoting BC development and progression. Wu et al. found that BC cell apoptosis was regulated by miR-380-3p [145]. Moreover, through its overexpression with precursors, miR-182-5p inhibits the apoptosis of BC cells [34]. Additional studies showed that BC cell chemoresistance was linked to the miRNA-mediated regulation of apoptosis. According to Zhan et al. [146], miR203 overexpression directly targeted B-cell lymphoma (Bcl)-w from the Bcl-2 family and survivin of the inhibitory apoptosis protein family to promote apoptosis, thereby enhancing the sensitizing effect of cisplatin.
PTEN, a bispecific phosphatase, controls growth, invasion, apoptosis, and differentiation via negative regulation of the phosphatidylinositol 3-kinase (PI3K)/AKT kinase-transforming protein (Akt) signaling pathway; it also prevents phosphorylation of Akt by decreasing the lipid second messenger PIP3 level via dephosphorylation, and the unphosphorylated Akt inhibits apoptosis or cell proliferation [147]. The presence of extracellular matrix proteins and multiple growth factors activates the PI3k/Akt oncogenic signaling pathway, and the PTEN/PI3K/Akt mTOR signaling pathway plays a critical part in BC development [147], [148], [149]. miR-222 stimulates the Akt/mTOR pathway and suppresses cisplatin-induced autophagy directly in BC cells [150]. Various miRNAs, including miR-130, miR-21, and miR-19a, can target PTEN [151], [152], [153].
miRNA-mediated regulation of BC cell cycle
The study of cell cycle is currently a research hotspot. miRNAs regulate the cell cycle to affect the chemoresistance of BC cells; for example, miR-150-5p expression downregulation accelerates the cell cycle progression and proliferative potential of BC cells [154]. Numerous studies indicated that miRNAs regulate cell cycle as well as chemoresistance by altering cyclin-dependent kinases (CDKs) and p27, for example, miR-124, miR-29c, and miR-195 can target CDKs [155], [156], [157], while miR-192 and miR-221 can target p27 [158]. miR-34a, the downstream effector of p53, regulates cell cycle and influences chemoresistance by inhibiting CDK6; furthermore, NAD-dependent histone deacetylase sirtuin-1 affects the cell cycle, which eventually makes cancer cells more sensitive to cisplatin [159]. Similarly, miR-196a-5p inhibits cisplatin/gemcitabine-induced apoptosis in UCA1 cells by targeting and inhibiting p27, a downstream effector of p53 [74]. These results confirm that miRNAs regulate the chemosensitivity of BC cells through a complex network system and that any component of the target gene axis of miRNAs could function as a target for tumor therapy; therefore, the complex network regulatory axis should be further investigated.
miRNA-mediated regulation of EMT in BC
In the complex EMT process, epithelial cells acquire various characteristics of mesenchymal cells, such as invasiveness and motility [160]. These characteristics can be reversed as cells can regain epithelial phenotypes through MET (mesenchymal-epithelial transformation), which enables cancer cells to relocate to distant metastatic sites [161]. Evidence suggests that EMT enables to malignant cancers to invade and proliferate, including BC [162, 163]. The determination of signaling pathways involved in directing epithelial cell activation toward EMT in tumor invasion and other malignant diseases can provide insights into cellular phenotypes’ plasticity [164].
Molecularly, EMT shows E-cadherin absence and high levels of transcriptional repressors of E-cadherin, for example, ZEB1, ZEB2, Twist, SNAIL, and Slug [165, 166]. The chemoresistance of BC cells is facilitated by the EMT-like phenotype [167]. The tumor suppressor gene ERBB receptor feedback inhibitor 1 (ERRFI-1) can be a target for miR-200; furthermore, miR-200 stable expression enhances E-calmodulin level in BC cells; decreases the levels and cell migration of ZEB1, ZEB2, and ERRFI-1; and makes BC cells more sensitive to epidermal growth factor receptor blockers [168]. Among them, Twist-related protein 1 (Twist1) is a direct target for miR-203; this miRNA exerts tumor suppressive effects by negatively targeting Twist1 [169]. mitogen-activated protein kinase (MAPK) and SNAIL are the direct target genes for miR-22. The overexpression of MAPK1 is related to poor survival of cancer patients; it induces Slug transcriptional activity and increases vimentin level, whereas miR-22 overexpression reverses migration and invasion induced by MAPK or SNAIL, thus playing a critical role in the MAPK1/Slug/vimentin feedback loop as well as EMT progression [46]. Several other miRNAs are also linked to BC cell migration, invasion, proliferation, and EMT. miR-323a-3p overexpression significantly inhibited EMT progression in BC, and both MET and mothers against decapentaplegic homolog 3 (SMAD3) were the direct targets for miR-323a-3p; furthermore, MET and SMAD3 knockdown was consistent with the overexpression of miR-323a-3p for suppressing EMT progression of BC [75]. In vitro and in vivo experiments revealed that miR-381-3p overexpression remarkably reduced cell proliferation by downregulating EMT progression induced by MET and CCNA2 and inducing G1 phase block and migration [170]. miR-665 expression in the miRNA cluster of DLK1-DIO3 was downregulated by the upstream methylation process in BC, and miR-665 overexpression markedly downregulated SMAD3 and phosphorylated SNAIL and SMAD3, thereby reversing EMT and inhibiting BC cell migration [171]. The downstream target genes of miR-433 are c-Met and CREB1, and miR-433 prevents EMT in BC cells through controlling the c-Met/Akt/GSK-3β/SNAIL signaling pathway [82]. Similar to miR-22, miR-199-5p, miR-92b, miR-451, and miR-301b are associated with EMT in BC cells [46, 81, 172], [173], [174].
Regular and systematic chemotherapy can reduce the incidence of tumor recurrence, suppress tumor progression, and increase BC patients’ survival rate [6]. However, the number of BC patients who are resistant to chemotherapeutic drugs is increasing; this phenomenon leads to tumor recurrence and progression and thus becomes a hindrance to develop appropriate treatment strategies for BC. As we continue to reveal the specific mechanisms by which miRNAs induce BC cells to become sensitive or resistant to chemotherapeutic drugs, miRNAs could function as potential targets for treating patients having chemoresistant BC and prolong their survival.
Conclusions
This review summarizes the functions of aberrantly expressed miRNAs in blood and urine of patients with BC by analyzing relevant studies and providing insights to explore the mechanisms of BC development and identify new tumor markers. Additionally, the review investigates the relationship between dysregulated miRNAs and the pathological classification of BCs to provide a relevant foundation to diagnose and prognose BC. Finally, the review discusses how dysregulated miRNAs affect chemotherapy resistance development in BC cells. These insights will help clinicians to find new targets for treating BC and thus develop improved treatment strategies for patients with BC.
Because BC cells can rapidly proliferate and metastasize to other body parts via blood vessels, which results in a high mortality rate, it is critical to develop appropriate treatment approaches to effectively reduce the invasion and proliferation ability of BC cells in future studies. Furthermore, the lack of innovation in the search for new treatment strategies for BC and challenges such as drug resistance and radioresistance also need to be addressed. The functions and specific mechanisms of action for several miRNAs remain unclear; moreover, many contradictory findings exist. Multiple studies have primarily investigated the molecular mechanisms, and the important function of miRNAs in BC to guide its diagnosis and treatment remains to be translated in clinical practice. Thus, additional studies to clarify the mechanisms of BC development and to implement effective therapeutic and preventive measures are required. More accurate and systematic tests will generate new ideas for the prognosis, diagnosis, and treatment of BC patients.
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Research funding: The present study was funded by the Youth Talents of the Hubei Provincial Health Council (Grant No. WJ2021Q014).
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Author contributions: Study concept and design: YX; data collection: XWP and CQX; analysis and interpretation of results: CG, FG, and YW; draft manuscript preparation: HH. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Not applicable.
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Ethical approval: Not applicable.
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Availability of data and materials: All data generated or analyzed during this study are included in this published article.
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Articles in the same Issue
- Frontmatter
- Review Article
- Differential expression and functions of miRNAs in bladder cancer
- Research Articles
- Pan-cancer analysis, providing a reliable basis for IDO2 as a prognostic biomarker and target for immunotherapy
- Knockdown of pyruvate kinase M2 suppresses bladder cancer progression
- Development and validation of a nomogram for predicting survival in patients with pancreatic ductal adenocarcinoma after radical pancreatoduodenectomy
- SET domain containing protein 8 (SET8) promotes tumour progression and indicates poor prognosis in patients with laryngeal squamous cell carcinoma
- Hypoxia-inducible factor 1α (HIF-1α)-activated Gli1 induces invasion and EMT by H3K4 methylation in glioma cells
- The inhibitory effects of lobaplatin, or in combination with gemcitabine on triple-negative breast cancer cells in vitro and in vivo
- Case Report
- Epstein–Barr virus positive gastric adenocarcinoma with systemic EBV reactivation in a patient with persistently active systemic lupus erythematosus
Articles in the same Issue
- Frontmatter
- Review Article
- Differential expression and functions of miRNAs in bladder cancer
- Research Articles
- Pan-cancer analysis, providing a reliable basis for IDO2 as a prognostic biomarker and target for immunotherapy
- Knockdown of pyruvate kinase M2 suppresses bladder cancer progression
- Development and validation of a nomogram for predicting survival in patients with pancreatic ductal adenocarcinoma after radical pancreatoduodenectomy
- SET domain containing protein 8 (SET8) promotes tumour progression and indicates poor prognosis in patients with laryngeal squamous cell carcinoma
- Hypoxia-inducible factor 1α (HIF-1α)-activated Gli1 induces invasion and EMT by H3K4 methylation in glioma cells
- The inhibitory effects of lobaplatin, or in combination with gemcitabine on triple-negative breast cancer cells in vitro and in vivo
- Case Report
- Epstein–Barr virus positive gastric adenocarcinoma with systemic EBV reactivation in a patient with persistently active systemic lupus erythematosus
