ABSTRACT
BACKGROUND: ATP-binding cassette (ABC) transporters play a crucial role in the development of multidrug resistance in diverse cancer entities. OBJECTIVE: Our study was designed to comprehensively analyze the ABC subfamily B (ABCB) in renal cell carcinoma (RCC) using The Cancer Genome Atlas (TCGA) datasets. DESIGN, SETTING, AND PARTICIPANTS: We performed systematic survival analyses of ABCB1-10 using the TCGA datasets for clear cell, papillary, and chromophobe RCC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Results were validated via quantitative polymerase chain reaction in a clear cell RCC (ccRCC) cohort containing 152 samples. Afterward, ABCB8 protein expression was assessed in a tissue microarray RCC cohort (n = 144) by immunohistochemistry with subsequent quantitative image analysis. In vitro, antisense oligonucleotide-induced ABCB8 knockdowns were established in ACHN and CAKI1 following functional analyses. RESULTS AND LIMITATIONS: Various ABCB members have prognostic value among the three most occurring RCC subtypes. Of note, ABCB8 was identified as the most prognostic ABCB gene in the RCC TCGA cohorts. Further, ABCB8 proved to be an independent predictor of shortened cancer-specific survival in three independent cohorts. In vitro, specific ABCB8 knockdown reduced viability and migration capacity in ACHN and CAKI1. CONCLUSIONS: ABCB8 was identified as a promising prognostic biomarker. Functional analyses suggest a tumor-promoting role of ABCB8 in ccRCC. PATIENT SUMMARY: In this study, the transporter gene ABCB8 proved to be a risk predictor of a worse clinical course in clear cell renal cell carcinoma. In the renal cell carcinoma cell culture model, depletion of this gene led to a reduction in the malignant potential, and inhibition of this gene may therefore possess a therapeutic value.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Adenosine Triphosphate , Carcinoma, Renal Cell/pathology , Genome , Humans , Kidney Neoplasms/pathology , PrognosisABSTRACT
Clear cell renal cell carcinoma (ccRCC) is among the most common human malignancies. Long non-coding RNAs (lncRNA) regulate various cellular functions and have been implicated in ccRCC pathogenesis. In order to decipher the molecular biology of this tumor and to identify potential prognostic biomarkers and therapeutic targets, we re-evaluated published lncRNA expression profiling data. An expression profile of 49 lncRNAs allowed discrimination of localized and advanced ccRCC. The expression profile of six lncRNAs transcripts (lnc-ACO1625, lnc-CYP4A22-2/3, lnc-PEAK1.1-1, lnc-PCYOX1L, lnc-VCAN-1, lnc-ZNF180-2) with potential prognostic interest were validated in a cohort of 50 normal renal, 57 localized ccRCC and 45 advanced ccRCC tissues. lnc-ZNF180-2 levels were similar in localized ccRCC and normal renal tissue, but we observed a significant increase of lnc-ZNF180-2 expression in advanced ccRCC tissue. Furthermore, lnc-ZNF180-2 expression levels were an independent predictor of progression-free survival, cancer-specific survival and overall survival in ccRCC patients. We also observed that lnc-CYP4A22-2/3 expression levels allowed discrimination of ccRCC and normal renal tissue. In conclusion, lncRNAs are involved in renal carcinogenesis, and quantification of lnc-ZNF180-2 may be useful for the prediction of ccRCC patients outcome following nephrectomy.
ABSTRACT
PURPOSE: Earlier studies indicate that epigenetics contribute to the pathogenesis of penile squamous cell carcinoma. Histone methylation patterns are frequently altered during carcinogenesis. Therefore, we investigated the methylation pattern of the histones H3K4, H3K9 and H3K27 in penile carcinoma and normal tissue. MATERIALS AND METHODS: A tissue microarray was constructed with 65 penile carcinomas, 6 metastatic lesions and 30 control tissues. Global histone methylation was assessed using immunohistochemistry. RESULTS: Global levels of H3K4me1, H3K9me1, H3K9me2, H3K27me2 and H3K27me3 were decreased, whereas H3K9me3 was increased in penile carcinoma. Histone methylation levels defined an epigenetic entity that allowed accurate differentiation of cancer and normal samples. We observed no correlation of histone methylation levels with clinicopathological parameters or patient outcome. CONCLUSIONS: The description of a definite epigenetic entity in penile carcinoma provides a rationale for testing epigenetic agents in patients with metastatic disease.
