Bladder cancer (BC) and renal cell carcinoma (RCC) are frequently diagnosed urinary tract cancers, and ~429 000 and 338 000 new cases, respectively, were diagnosed worldwide in 2012.1 Recently developed molecular-targeted therapies for RCC have shown remarkable therapeutic efficacy; however, no targeted therapeutics are currently approved for the treatment of BC. Consequently, the survival rate for invasive BC has not improved in the past decade.

BC is the eighth leading cause of death in men in the United States of America, accounting for an estimated 4% of deaths in men in 2016.2 For non-muscle-invasive BC, transurethral surgical resection and intravesical installation of immunotherapeutic agents such as bacillus Calmette-Guerin or chemotherapeutic agents such as mitomycin C are the primary suggested treatments; however, the recurrence rate is high for this type of BC. Moreover, the prognosis of patients with muscle-invasive BC is poor, with a 5-year survival rate of <50%. Specifically, metastatic BC is difficult to treat, with a median survival of ~8 months without treatment and 14 months with treatment.3 Despite the high prevalence and mortality rates of BC, its molecular mechanisms are poorly understood and the primary approach to treat metastatic BC remains cisplatin-based conventional chemotherapy.

RCC accounts for over 80% of kidney cancers. Kidney cancer is the seventh leading cause of newly diagnosed cancer in the United States of America. The incidence of RCC is increasing because of recent improvements in screening methods; that is, ultrasound and computed tomography. In localized RCC, surgery is the standard curative treatment. Although recent molecular-targeted agents have improved prognoses in patients with advanced RCC, the 5-year survival rate is still low (12.3%) because of recurrence or distant metastasis.4 Therefore, understanding the molecular mechanisms underlying BC and RCC using current genomic technologies is urgently needed.

MicroRNAs (miRNAs) are a class of small (19–22 nucleotides) noncoding RNA molecules that regulate protein-coding/noncoding RNA expression in a sequence-dependent manner.5, 6 A large body of evidence has suggested that miRNAs are aberrantly expressed in many human cancers and are deeply involved in cancer pathogenesis.7, 8, 9 Some highly expressed miRNAs in cancer tissues may function as oncogenes by repressing tumor suppressors; conversely, miRNAs expressed at low levels in cancer tissues may function as tumor suppressors by negatively regulating oncogenes.7, 10 Aberrant expression of miRNAs may be caused by disruption of the RNA network in cancer cells.7, 9, 10 Therefore, identification of aberrantly expressed miRNAs in cancer cells may provide important insights into novel RNA networks in cancer cells. In this review, we summarize aberrantly expressed miRNAs based on current BC and RCC miRNA signatures.11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 We discuss the dysregulated expression of the miR-200 family and miR-200 family target genes in BC and RCC.

miRNA expression signatures in BC

We reviewed seven recently published miRNA expression signatures comparing BC and normal bladder epithelium (Table 1).11, 12, 13, 14, 15, 16, 17 The analysis platforms varied between studies. Two recent signatures were constructed from deep sequencing, and the other five signatures were constructed from microarray-based analyses. Array-based technologies rapidly identify differentially expressed miRNAs. However, detected miRNAs depend on the number of the probes mounted on the array. Recent development of deep-sequencing technologies proved the novel miRNAs and minor miRNAs such as passenger strands. Several studies demonstrated that passenger strands of miRNAs acted as tumor-suppressive miRNAs in several cancers.24, 25 In this review, to clearly summarize these miRNA signatures, we focused on commonly downregulated miRNAs or upregulated miRNAs regardless of the platforms and backgrounds of clinical tissues. We sorted these miRNAs by the number of studies because we assumed that miRNAs found in more signatures may have important roles in BC (Table 2).

Table 1 Differentially expressed miRNAs in BC
Table 2 Frequently down-or upregulated miRNAs in BC

Downregulated miRNAs in multiple BC signatures

Six of seven signatures showed downregulation of miR-125b and miR-143-3p in BC clinical tissues. Multiple articles described the tumor-suppressive role of miR-125b in BC, showing that this miRNA targeted oncogenes such as E2F3, SphK1, SIRT7, MALAT1 and MMP13.26, 27, 28, 29 miR-125b functions as a tumor suppressor in ovarian cancer, breast cancer, osteosarcoma and bladder cancer.26, 27, 28, 29, 30, 31, 32 However, in prostate cancer, glioma and leukemia, miR-125b functions as an oncogene by targeting tumor suppressors.33, 34, 35

miR-143-3p, miR-145-5p and miR-145-3p are clustered on chromosome 5q32, and multiple signatures have shown that these miRNAs are downregulated in BC. Putative oncogenes regulated by miR-143 or miR-145 in BC include ERK5, Akt, FSCN1, IGF1R, PAK1 and PAI-1.36, 37, 38, 39, 40 Interestingly, miRNAs in this cluster function as tumor suppressors in a variety of cancers, including BC, and few reports have described oncogenic roles of miR-143 or miR-145.40, 41, 42, 43 Thus, members of the miR-143/145 cluster commonly function as tumor suppressors, independent of the cancer type.

Upregulated miRNAs in multiple BC signatures

miR-20a-5p was the most frequently upregulated miRNA in BC (Table 2). miR-20a has an oncogenic function in colorectal cancer and gallbladder carcinoma,44, 45 but a tumor-suppressive function in hepatocellular carcinoma, oral squamous cell carcinoma and pancreatic carcinoma.46, 47, 48 miR-20a is clustered with miR-17/18a/19a/19b-1/92a-1 on chromosome 13q31.3; this cluster is known as the miR-17-92 cluster. Several reports have demonstrated the oncogenic function of this cluster in various types of cancers.49, 50, 51 Furthermore, miR-18a, miR-19a and miR-19b have also been shown to be upregulated in multiple BC profiles (Table 1). Additionally, upregulation of miR-19a in tissues and plasma samples from patients with BC has been reported, and this miRNA has been shown to act as an oncogene by targeting PTEN, which may have a significant role in human BC.52, 53

miRNA expression signatures of RCC

We also reviewed six recently published miRNA expression signatures comparing RCC and normal kidney tissue using clinical specimens (Table 3).18, 19, 20, 21, 22, 23 Two signatures were constructed from deep sequencing and the other four signatures were constructed from microarrays. Commonly downregulated miRNAs or upregulated miRNAs in multiple signatures are listed in Table 4, sorted according to the number of signatures.

Table 3 Differentially expressed miRNAs in RCC
Table 4 Frequently down-or upregulated miRNAs in RCC

Downregulated miRNAs in multiple RCC signatures

According to miRNA expression signatures in RCC, five of six signatures showed downregulation of miR-141 and miR-200c in RCC tissues compared with normal tissues (Table 4). miR-141 and miR-200c are clustered within 10 kbp. Recent studies have shown that these miRNAs are downregulated in several cancers, including RCC, and regulate the epithelial-to-mesenchymal transition (EMT) by targeting E-cadherin transcriptional repressors, such as zinc-finger E-box-binding homeobox 1 and 2 (ZEB1 and ZEB2).54, 55, 56, 57, 58 Furthermore, miR-429, the third most frequently downregulated miRNA in RCC, forms a cluster with miR-200a/200b, and miR-141/200c and miR-200a/200b/429 are members of the miR-200 family.55 The miR-200 family has been reported to be associated with the EMT, either inhibiting or inducing the EMT depending on the cancer type.55, 59 In RCC, many reports have indicated that miRNAs in this family have tumor-suppressive roles and inhibit the EMT.55, 60 Nakada et al.60 reported that miR-141 and miR-200c are downregulated in clear-cell RCC and that these miRNAs may be involved in suppression of CDH1/E-cadherin transcription by upregulation of ZFHX1B. These findings suggest the importance of the EMT-related miR-200 family in RCC oncogenesis and metastasis.

Upregulated miRNAs in multiple RCC signatures

Four of six signatures have shown upregulation of miR-155, miR-210 and miR-224 in RCC (Table 4).

Gao et al.61 reported that miR-155 contributes to the proliferation and invasion of clear-cell RCC by directly targeting E2F2, which has crucial roles in the regulation of cell proliferation. Upregulation of miR-155 has also been found in several other types of cancer, such as colorectal cancer, breast cancer and lymphoma.62, 63, 64

miR-210 has been reported to function as an oncogene and have applications as a potential serum biomarker in RCC. Interestingly, miR-210 has been reported to be a hypoxia-inducible miRNA. Given the key roles of the VHL-HIF pathway in RCC, the upregulation of miR-210 may be one of the central mechanisms of RCC oncogenesis. miR-210 is also frequently upregulated in other cancer tissues and has been shown to have an oncogenic function in other human cancers, including BC (Table 2).65, 66, 67, 68, 69, 70, 71

miR-224 has an oncogenic function in colorectal cancer, lung cancer, esophageal squamous cell carcinoma and RCC,72, 73, 74, 75, 76 but a tumor-suppressive function in prostate cancer.77 Cheng et al.76 reported that miR-224 was upregulated in clear-cell RCC and directly targeted type 1 iodothyronine deiodinase.75

Comparison of miRNA expression signatures in BC and RCC

Careful analysis of Tables 2 and 4 showed that some members of the miR-200 family (miR-141/200c and miR-200a/200b/429) are frequently upregulated in BC, but are frequently downregulated in RCC. This phenomenon indicates that these miRNAs have opposing roles in RCC and BC. Furthermore, these miRNAs may target tumor suppressors in BC and oncogenes in RCC.

The members of the miR-200 family are clustered on two different chromosomal regions: miR-141 and miR-200c are on chromosome 12p13.31, whereas miR-200a, miR-200b and miR-429 are on chromosome 1p36.33. Additionally, members of the miR-200 family are classified into two groups (miR-141/200a and miR-200b/c/429) according to their seed sequence.

In cancer, the promoter region of the miR-141/200c cluster is hypermethylated, and the miR-200a/200b/429 cluster is silenced through polycomb group-mediated histone modifications.78, 79, 80 Recent studies indicated that several types of transcription factors bound to the promoter region of miR-200 family and these transcription factors regulated the transcription of the miR-200 family positively or negatively. Among them, Krüppel-like factor 5 positively regulates the transcription of the miR-200 family.81 In contrast, ZEB1, ZEB2 and B lymphoma Mo-MLV insertion region 1 homolog negatively regulate the transcription of miR-200 family.82, 83 To investigate the expression levels of these transcriptional factors, we used gene expression omnibus (GEO) database. According to these database, Krüppel-like factor 5 was downregulated in RCC compared with normal kidney tissue (GEO accession nos. GSE22541 and GSE36895). Furthermore, ZEB1, ZEB2 and B lymphoma Mo-MLV insertion region 1 homolog were downregulated in BC tissue compared with normal bladder epithelium (GEO accession nos. GSE11783 and GSE31684). Aberrant expression of transcription factors may have an influence on the expression status of the miR-200 family in BC and RCC.

Next, we analyzed putative target genes for miR-200 family in these two cancers. We performed genome-wide gene expression analysis and in silico analysis. First, we screened putative target genes of the miR-200 family using TargetScan Release 7.0 (Whitehead Institute for Biomedical Research, Cambridge, MA, USA). Next, we analyzed a publicly available gene expression data set in the GEO database of BC and RCC (accession number: GSE36895, GSE22541, GSE11783 and GSE31684). To select putative genes that function as tumor suppressors in BC and oncogenes in RCC, we screened downregulated genes in BC compared with normal bladder epithelium (average log FC <−1) and upregulated genes in RCC compared with normal kidney tissue (average log FC >1). We merged these data sets, and 17 putative genes were identified (Table 5). These genes were sorted by the difference between expression in RCC and BC. TRPA1 was upregulated in RCC and downregulated in BC and has putative target sites for members of the miR-200 family. Therefore, we speculated that TRPA1 may be critical in RCC and BC oncogenesis based on this search of miR-200 family-regulated genes.

Table 5 Putative target genes of the miR-200 family in RCC and BC

TRPA1 is a member of the transient receptor potential (TRP) cation channel subfamily. Although transient receptor potential channels function as key regulators of oncogenesis and metastasis, their oncogenic and tumor-suppressive roles are not consistent among different types of cancers.84 As shown in Table 5, TRPA1 may function as an oncogene in RCC but a tumor suppressor in BC. Furthermore, Veldhuis et al. reported that transient receptor potential and G-protein-coupled receptors function independently and synergistically to excite sensory nerves.85 G-protein-coupled receptors are seven-transmembrane-spanning receptors that modulate several biological functions, including cancer progression.86, 87 Several G-protein-related genes (RGS5, GPR, RGS18 and GNG2) have been shown to be upregulated in RCC and downregulated in BC (Table 5). Therefore, we hypothesize that G-protein-coupled receptor-transient receptor potential channel interactions may be key regulators of downstream signaling (oncogenic or tumor-suppressive pathways) in these two types of urinary tract cancers.


A growing body of evidence has shown that various aberrantly expressed miRNAs contribute to BC and RCC pathogenesis. The discovery of noncoding RNA in the human genome has provided evidence of the complexity of the RNA network in normal and cancer cells. For further elucidation of novel RNA networks in cancer cells, miRNA information will need to be organized based on expression signatures. The present review highlighted recent findings of the aberrant expression of miRNAs in BC and RCC cells. The discovery of miRNA-regulated RNA networks in cancer cells has provided new opportunities for strategies in cancer diagnosis and treatment.