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Independent verification of circulating miRNA as diagnostic biomarkers for urothelial carcinoma.

ABSTRACT: Urothelial carcinoma (UC) is an umbrella term for bladder cancers (BCa) and upper-tract urothelial carcinoma (UTUC), with BCa and UTUC sometimes detected concomitantly. The methods of detection for UC are often inaccurate or highly invasive, and, therefore, are thought to be unsatisfactory. Previously, we reported seven serum miRNAs as diagnostic markers for BCa. Here, we re-evaluated potential diagnostic miRNAs in different institutions. We prospectively analyzed serum samples obtained from 126 UC patients (BCa: 106 samples; UTUC: 14 samples; UTUC with BCa: six samples) and 50 noncancer controls by microarray analysis. We randomly assigned these samples into a training or a validation set. Biomarker candidate miRNAs were selected based on cross-validation scores in the training set of samples, with diagnostic power confirmed in the validation set. Among the diagnostic miRNAs identified in this way, miR-1343-5p and miR-6087 had been identified as potential diagnostic miRNAs in our previous study. In addition, we evaluated the association between the serum levels of identified miRNAs and the presence of UC risk conditions. The expression levels of several miRNAs correlate with the risk factors in participants without UC, which may be explained by the presence of a microscopic tumor or a precancerous lesion. In conclusion, we identified two robust miRNA diagnostic markers for UC detection. Further functional analysis is required to elucidate the mechanism by which alterations in the expression of these miRNAs occur.

SUBMITTER: Urabe F

PROVIDER: S-EPMC9530882 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Independent verification of circulating miRNA as diagnostic biomarkers for urothelial carcinoma.

Urabe Fumihiko F Matsuzaki Juntaro J Takeshita Fumitaka F Kishida Takeshi T Ochiya Takahiro T Hirai Kotaro K

Cancer science 20220812 10

Urothelial carcinoma (UC) is an umbrella term for bladder cancers (BCa) and upper-tract urothelial carcinoma (UTUC), with BCa and UTUC sometimes detected concomitantly. The methods of detection for UC are often inaccurate or highly invasive, and, therefore, are thought to be unsatisfactory. Previously, we reported seven serum miRNAs as diagnostic markers for BCa. Here, we re-evaluated potential diagnostic miRNAs in different institutions. We prospectively analyzed serum samples obtained from 126 ...[more]

PMID: 35848873

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Project description:Many long noncoding RNAs (lncRNAs) are deregulated in cancer and contribute to oncogenesis. In urothelial carcinoma (UC), several lncRNAs have been reported to be overexpressed and proposed as biomarkers. As most reports have not been confirmed independently in large tissue sets, we aimed to validate the diagnostic and prognostic value of lncRNA upregulation in independent cohorts of UC patients. Thus, expression of seven lncRNA candidates (GAS5, H19, linc-UBC1, MALAT1, ncRAN, TUG1, UCA1) was measured by RT-qPCR in cell lines and tissues and correlated to clinicopathological parameters including follow-up data (set 1: N n = 10; T n = 106). Additionally, publicly available TCGA data was investigated for differential expression in UC tissues (set 2: N n = 19; T n = 252,) and correlation to overall survival (OS). All proposed candidates tended to be upregulated in tumour tissues, with the exception of MALAT1, which was rather diminished in cancer tissues of both data sets. However, strong overexpression was generally limited to individual tumour tissues and statistically significant overexpression was only observed for UCA1, TUG1, ncRAN and linc-UBC1 in tissue set 2, but for no candidate in set 1. Altered expression of individual lncRNAs was associated with overall survival, but not consistently between both patient cohorts. Interestingly, lower expression of TUG1 in a subset of UC patients with muscle-invasive tumours was significantly correlated with worse OS in both cohorts. Further analysis revealed that tumours with low TUG1 expression are characterized by a basal-squamous-like subtype signature accounting for the association with poor outcome. In conclusion, our study demonstrates that overexpression of the candidate lncRNAs is found in many UC cases, but does not occur consistently and strongly enough to provide reliable diagnostic or prognostic value as an individual biomarker. Subtype-dependent expression patterns of lncRNAs like TUG1 could become useful to stratify patients by molecular subtype, thus aiding personalized treatments.

Project description:We investigated the expression profiles of microRNAs (miRNA) in 26 renal cell carcinoma (RCC) FFPE tissues (3 chRCC, 5 papRCC and 18 ccRCC), 4 urothelial cell carcinomas of the upper urinary tract (UT-UCs) and 20 normal kidneys by using the miRCURY LNA™ microRNA Array, 6th gen (Exiqon, Woburn MA), containing capture probes that target all miRNAs for all species registered in the miRBASE version 16.0. Real-time PCR (qRT-PCR) using appropriate endogenous controls was performed in order to validate the microarray results of the 27 most differentially expressed (DE) miRNAs. We identified 434 miRNAs that were significantly deregulated in all tumours compared to the normal kidney tissues. Overall, 126 miRNAs (29%) showed increased expression and 303 miRNAs (69.8%) had decreased expression in RCCs and UT-UCs vs. the normal kidneys. Specifically, 374, 420, 421 and 409 miRNAs were 90% consistently down-regulated in ccRCC, papRCC, chRCC and UT-UC, respectively. Unsupervised two-way hierarchical clustering (HCL) with Euclidian distance accurately discriminated between RCC and UT-UC. Apart from one chRCC sample that was clustered with ccRCCs, HCL also managed to successfully classify the 3 RCC subtypes among them. Furthermore, it showed that ccRCC is more closely related to papRCC and that both are distinct from chRCC or UT-UC. Ninety-four miRNAs were co-upregulated among ccRCC, papRCC and chRCC; and 11, 44 and 24 miRNAs were specifically up-regulated in each one of the three RCC subtypes (ccRCC, chRCC and papRCC), respectively. On the other hand, 222 miRNAs were co-down-regulated in the three RCC subtypes, whereas 16, 18 and 5 miRNAs were specifically down-regulated in ccRCC, chRCC and papRCC, respectively. When the DE miRNAs in each RCC subtype were combined with those in UT-UC, we identified 89 and 206 miRNAs, respectively, that were up- and down-regulated in all tumor types. miRNA profiling can distinguish between RCC and UT-UC as well as among distinct RCC subtypes. Our data validicate that miRNA expression tends to be down-regulated in RCC versus the normal kidney tissue.

Project description:BackgroundEarly detection and diagnosis of malignant tumors is critical for improving the survival rate and treatment outcomes of oral cancer. Thus, the current prospective investigation was designed to verify the role, sensitivity, and specificity of salivary LINC00657 and miRNA-106a as diagnostic markers in oral squamous cell carcinoma patients as compared to oral lichen planus (as an example of oral potentially malignant disorders) and normal individuals, and to show LINC00657 relation to miR-106a.MethodsA total of 36 participants were included, subdivided into 3 groups: Group I: 12 patients diagnosed with oral squamous cell carcinoma (OSCC). Group II: 12 patients diagnosed with oral lichen planus (OLP). Group III: 12 systemically free individuals with no oral mucosal lesions. Unstimulated salivary samples were collected from all participants to evaluate level of LINC00657 and miR-106a in different groups using quantitative real-time PCR.ResultsOSCC showed the highest LINC00657 and lowest miR-106a fold change among included groups. Receiver Operating Characteristic (ROC) curve analysis of the two biomarkers for detecting OSCC revealed that LINC00657 had higher diagnostic accuracy (DA) (83.3%) compared to miR-106a (80.4%). As for detecting OLP, ROC analysis showed that miR-106a had higher (DA) (61%) compared to LINC00657 (52.5%). To discriminate OSCC from OLP, the diagnostic accuracy of both markers is the same (75%). Moreover, differentiating OSCC grades II and III, ROC analysis showed that miR-106a had lower (DA) (60%) compared to LINC00657 (DA) (83.3%).ConclusionsSalivary LINC00657 and miR-106a could be promising diagnostic markers for oral squamous cell carcinoma. Salivary LINC00657 may differentiate oral squamous cell carcinoma from oral potentially malignant disorders with considerable diagnostic accuracy. Moreover, low levels of salivary miR-106a could have the potential to indicate malignancy.Trial registrationThe study was retrospectively registered on clinicaltrial.gov with NCT05821179 (first trial registration in 26/3/2023), date of registration: 19/4/2023.

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Independent verification of circulating miRNA as diagnostic biomarkers for urothelial carcinoma.

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Independent verification of circulating miRNA as diagnostic biomarkers for urothelial carcinoma.

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