Downregulation of HNF-1B in Renal Cell Carcinoma Is Associated With Tumor Progression and Poor Prognosis

Büchner, Alexander; Castro, Mirna; Hennig, Anja; Popp, Tanja; Assmann, G.; Stief, Christian G.; Zimmermann, Wolfgang

doi:10.1016/j.urology.2010.03.042

Cited by 33 publications

(38 citation statements)

References 29 publications

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“…HNF1B underexpression and biallelic inactivation were repeatedly observed in small case reports and case series of ChRCC (23) (24) (25) (26) (27) We queried the ChRCC TCGA database, which includes 66 samples with RNAseq and mutation data, all of which have clinical information available. When we compared HNF1B mRNA levels in normal (N=25) and in ChRCC (N=66) specimens, we observed a significant reduction in mRNA levels (fold change= − 4.3 or 23% of normal, P =3.24e-8, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…During the same year, another report identified biallelic inactivation of HNF1B in two out of 12 patients with ChRCC (25). More recently, downregulation of HNF1B mRNA and protein was reported in an additional cohort of patients with ChRCC (26) (27), suggesting deficiency of HNF1B expression might play a significant role in the pathogenesis of ChRCC.…”

Section: Introductionmentioning

confidence: 97%

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HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas

et al. 2017

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Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell cycle checkpoint proteins RB1 and p27. Further, it altered the chromatin accessibility of Mad2l1, Bub1b and Rb1 genes and triggered aneuploidy development. Analysis of the TCGA database revealed TP53 mutations in 33% of ChRCC where HNF1B expression was repressed. In clinical specimens, combining HNF1B loss with TP53 mutation produced an association with poor patient prognosis. In cells, combining HNF1B loss and TP53 mutation increased cell proliferation and aneuploidy. Our results show how HNF1B loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of HNF1B and TP53 may enhance cellular survival and confer an aggressive phenotype in ChRCC.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas

et al. 2017

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“…7 A conditional liver-specific inactivation of the HNF1β gene resulted in abnormalities of the gallbladder and IHBDs and paucity of the small IHBD. 7 HNF1β expression has been reported in prostatic, 26 ovarian, 27 and renal cancers 28 but not in melanomas or breast, colorectal, lung, or pancreatic cancers. 29 Although a study reported HNF1β expression in human HCCs, 15 its clinicopathological implications remained largely unclear.…”

Section: Discussionmentioning

confidence: 98%

Expression of Bile Duct Transcription Factor HNF1β Predicts Early Tumor Recurrence and Is a Stage-Independent Prognostic Factor in Hepatocellular Carcinoma

Yuan

Lai

Hsu

et al. 2014

Journal of Gastrointestinal Surgery

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“…Epigenetic inactivation of HNF1B occurs in colorectal cell lines (Terasawa et al, 2006). Down-regulation or loss of expression of HNF1B is correlated with malignant transformation and dedifferentiation (Buchner et al, 2010). TATA element modulatory factor (TMF) is a Golgi-associated protein whose level is down-regulated in solid tumors; it shows antiangiogenic activity (Abrham et al, 2009).…”

Section: Mirna Profiling In Mutated Kras Versus Wildtype Krasmentioning

confidence: 99%

MicroRNA profiling differentiates colorectal cancer according to KRAS status

Mosakhani

Sarhadi

Borze

et al. 2011

Genes Chromosomes & Cancer

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Recent studies have shown the important role of microRNAs (miRNAs) in a variety of biological processes, and in its ability to distinguish tumors according to their prognostic and predictive properties. To identify miRNA signatures associated with colorectal carcinoma (CRC) and with KRAS status, we studied, using Agilent's miRNA microarrays, miRNA expression in primary tumors from 55 metastatic CRC patients, including 15 with mutant and 40 with wild-type KRAS. Comparing these with normal colon tissue, we identified 49 miRNAs-including 19 novel miRNAs-significantly deregulated in tumor tissue. The presence of the KRAS mutation was associated with up-regulation of miR-127-3p, miR-92a, and miR-486-3p and down-regulation of miR-378. Increased expression of miR-127-3p and miR-92a in KRAS mutant tumors was significantly confirmed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) (P < 0.05). We identified some predicted target genes of differentially expressed miRNAs between mutated and wild-type KRAS, such as RSG3 and TOB1, which are involved in apoptosis and proliferation. Target prediction and pathway analysis suggest a possible role for deregulated miRNAs in nicotinamide adenine dinucleotide phosphate (NADPH) regeneration and G protein-coupled receptor signaling pathways.

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Downregulation of HNF-1B in Renal Cell Carcinoma Is Associated With Tumor Progression and Poor Prognosis

Cited by 33 publications

References 29 publications

HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas

HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas

Expression of Bile Duct Transcription Factor HNF1β Predicts Early Tumor Recurrence and Is a Stage-Independent Prognostic Factor in Hepatocellular Carcinoma

MicroRNA profiling differentiates colorectal cancer according to KRAS status

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