POLR1D promotes colorectal cancer progression and predicts poor prognosis of patients

Wang, Mingqing; Niu, Wenbo; Hu, Rong; Wang, Yanjing; Liu, Yangyang; Liu, Lingyu; Zhong, Juan; Cha, Zhang; You, Hyun Ju; Zhang, Jiaxing; Lu, Lu; Wei, Lianbo; Xiao, Wei

doi:10.1002/mc.22966

Cited by 22 publications

(22 citation statements)

References 39 publications

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“…RNA polymerase I is involved in the production of 18S, 5.8S, and 28S rRNAs, while RNA polymerase III synthesizes small RNAs [50]. Despite a recent report describing the frequent overexpression of POLR1D in CRC [51], a role of POLR1D in cancer has not otherwise been thoroughly described in the literature.…”

Section: Amplicon Is Associated With Late-stage Clinical Featuresmentioning

confidence: 99%

Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer

et al. 2020

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Background: Bevacizumab, a monoclonal antibody against soluble VEGFA, is an approved and commonly administered anti-angiogenic drug in patients with metastasized colorectal cancer (mCRC). The survival benefit of anti-VEGF therapy in mCRC patients is limited to a few months, and acquired resistance mechanisms are largely unknown. Here, we employed whole-genome sequencing of plasma DNA to evaluate the tumor genome of patients undergoing treatment with bevacizumab to determine novel aberrations associated with resistance. Methods: Using longitudinal plasma analyses, we studied the evolution of tumor genomes in a mCRC cohort (n = 150) and conducted analyses of CRC cases from The Cancer Genome Atlas (TCGA) database (n = 619) to identify associations between genomic aberrations and clinical features. We employed whole-genome sequencing to identify the most frequently occurring focal somatic copy number alterations (SCNAs). Using the TCGA data as a comparative and supporting dataset, we defined the minimally amplified overlapping region and studied the mechanistic consequences of copy number gain of the involved genes in this segment. In addition, we established an in vitro cell model and conducted downstream gene expression and cell viability assays to confirm our findings from the patient dataset. Results:We observed a recurrent focal amplification (8.7% of cases) on chromosome 13q12.2. Analysis of CRC cases from the TCGA database suggested that this amplicon is associated with more advanced stages. We confirmed that this 13q12.2 amplicon frequently emerges later during the clinical course of disease. After defining the minimally amplified region, we observed that the amplification and expression of one gene, POLR1D, impacted cell proliferation and resulted in upregulation of VEGFA, an important regulator of angiogenesis which has been implicated in the resistance to bevacizumab treatment. In fact, in several patients, we observed the emergence of this 13q12.2 amplicon under bevacizumab treatment, which was invariably associated with therapy resistance. Conclusions: Non-invasive analyses of cell-free DNA from patients undergoing treatment with bevacizumab enabled the tracking of evolving tumor genomes and helped identify a recurrent focal SCNA of clinical relevance. Here, we describe a novel resistance mechanism against a widely applied treatment in patients with mCRC which will impact the clinical management of patients.

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Section: Amplicon Is Associated With Late-stage Clinical Featuresmentioning

confidence: 99%

Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer

et al. 2020

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“…It has been well documented that resistance to apoptosis caused by several genetic aberrations may promote the uncontrolled growth, invasion and metastasis of cancer cells . A previous study by Wang et al showed that the aberrant expression of RNA polymerase I subunit D inhibited cell apoptosis, but promoted cell proliferation and migration through the regulation of Wnt‐β‐catenin and p53 signalling pathways . Xiao et al indicated that rafoxanide promoted apoptosis by the inactivation of p38 MAPK pathway in myeloma .…”

Section: Discussionmentioning

confidence: 99%

“…**P < .01, ***P < .001 vs the NC group cells. 15 A previous study by Wang et al showed that the aberrant expression of RNA polymerase I subunit D inhibited cell apoptosis, but promoted cell proliferation and migration through the regulation ofWnt-β-catenin and p53 signalling pathways 16. Xiao et al indicated that rafoxanide promoted apoptosis by the inactivation of p38 MAPK pathway in myeloma 17.…”

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confidence: 98%

MicroRNA‐378‐3p/5p represses proliferation and induces apoptosis of oral squamous carcinoma cells via targeting KLK4

Cui

Bao

Liu

et al. 2020

Clin Exp Pharma Physio

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Oral squamous cell carcinoma (OSCC) is one of the most common types of head and neck neoplasm. Down‐regulation of hsa‐microRNA‐378 (miR‐378) has been proved in OSCC tissues, suggesting that miR‐378 might play crucial roles in the progression of OSCC. The present study aimed to evaluate the effect of miR‐378‐3p/5p on the proliferation and apoptosis of OSCC in vitro and in vivo. According to the results, lentivirus‐mediated overexpression of miR‐378 lowered the colony formation efficiency, blocked cell cycle progression, and decreased the percentage of Ki‐67 positive cells, whereas knockdown of miR‐378‐3p/5p led to the opposite results. Furthermore, the apoptosis of OSCC cells was induced by the overexpression of miR‐378 as evidenced by decreasing Bcl‐2/Bax ratio, increasing cleaved caspase‐9, cleaved caspase‐3, and cleaved PARP levels, and promoting the release of cytochrome c into the cytoplasm. However, the above results were reversed by miR‐378‐3p/5p silencing. In addition, the overexpression of miR‐378 inhibited the activation of PI3K/AKT signalling pathway. Conversely, miR‐378‐3p/5p knockdown resulted in the inactivation of PI3K/AKT signalling pathway. Mechanically, we validated that miR‐378‐3p/5p could target kallikrein‐related peptidase 4 (KLK4), and enforced overexpression of KLK4 counteracted miR‐378 overexpression‐induced apoptosis. Finally, tumourigenesis in nude mice was suppressed by the overexpression of miR‐378, which was promoted by miR‐378‐3p/5p silencing. Taken together, these results suggest that miR‐378 may be a potential target in the diagnoses and treatment of OSCC.

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“…That DNA-directed RNA polymerases (Pol I, Pol II and Pol III) is differentially expressed and deregulated has been detailed in multiple cancers [20]. POLR2K, a subunit of this polymerases, participates in multiple steps of transcription [21].In this paper, we initially discovered that POLR2K was overexpressed in 408 BLCA samples from the TCGA and that high POLR2K expression may serve as an indicator of poor survival.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression and Regulatory Webwork of POLR2K in Bladder Carcinogenesis by Integrated Bioinformatics Approaches

Yang

Wang

Guo

et al. 2020

Preprint

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Background：RNA polymerase II subunit K (POLR2K) belongs to one of the multiple subunits of RNA polymerase II (Pol II), whose biological function is to synthesize mRNA. Aberrant POLR2K expression is related to carcinogenesis. However, POLR2K’s underlying role in bladder cancer has not been explored. In the current study, we intend to analyze the function of POLR2K and its regulatory network within bladder cancer.Methods: Public sequencing data was obtained from GEO and TCGA to investigate POLR2K expression and regulatory network within bladder cancer (BLCA) by using GEPIA and Oncomine as well as cBioPortal online tool. LinkedOmics was employed to identify genes displaying significantly differential expression patterns and to perform GO and KEGG analyses. After differential genes was assigned and ranked, GSEA analyses was performed to obtain target networks for transcription factors, miRNAs, and kinases that could regulate POLR2K–associated gene network. Subsequent functional webwork analyses were used to identify cancer-relevant pathways Moreover, POLR2K gene is verified, by ChIP-seq in MCF-7 cell line , with transcription factor binding evidence in the ENCODE Transcription Factor Binding Site Profiles dataset.Conclusions: The current study implies that POLR2K gene is overexpressed and often amplified in BLCA, providing the first evidence that POLR2K deregulation, in particular increased transcription, may promote BLCA. These findings uncover a unique expression patterns of POLR2K and its potential regulatory networks in BLCA, contributing greatly to study of the role of POLR2K in cancer development.

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POLR1D promotes colorectal cancer progression and predicts poor prognosis of patients

Cited by 22 publications

References 39 publications

Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer

Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer

MicroRNA‐378‐3p/5p represses proliferation and induces apoptosis of oral squamous carcinoma cells via targeting KLK4

Gene Expression and Regulatory Webwork of POLR2K in Bladder Carcinogenesis by Integrated Bioinformatics Approaches

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