Pre-mRNA processing factor 19 functions in DNA damage repair and radioresistance by modulating cyclin D1 in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is known for its high mortality rate worldwide. Based on intensive studies, microRNA (miRNA) expression functions in tumor suppression. Therefore, we aimed to evaluate the contribution of miR-146a-5p to radiosensitivity in HCC through the activation of the DNA damage repair pathway by binding to replication protein A3 (RPA3). First, the limma package of R was performed to differentially analyze HCC expression chip, and regulative miRNA of RPA3 was predicted. Expression of miR-146a-5p, RPA3, and DNA damage repair pathway-related factors in tissues and cells was determined. The effects of radiotherapy on the expression of miR-146a-5p and RPA3 as well as on cell radiosensitivity, proliferation, cell cycle, and apoptosis were also assessed. The results showed that there exists a close correlation between miR-146a and the radiotherapy effect on HCC progression through regulation of RPA3 and the DNA repair pathway. The positive rate of ATM, pCHK2, and Rad51 in HCC tissues was higher when compared with that of the paracancerous tissues. SMMC-7721 and HepG2 cell proliferation were significantly inhibited following 8 Gy 6Mv dose. MiR-146a-5p restrained the expression of RPA3 and promoted the expression of relative genes associated with the DNA repair pathway. In addition, miR-146a-5p overexpression suppresses cell proliferation and enhances radiosensitivity and cell apoptosis in HCC cells. In conclusion, the present study revealed that miR-146a-5p could lead to the restriction of proliferation and the promotion of radiosensitivity and apoptosis in HCC cells through activation of DNA repair pathway and inhibition of RPA3.

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Ablating Ku70 phosphorylation results in defective DNA damage repair and spontaneous induction of hepatocellular carcinoma

10.1101/2021.03.03.433432 ◽

2021 ◽

Author(s):

Janapriya Saha ◽

Jinsung Bae ◽

Shih-Ya Wang ◽

Lori J. Chappell ◽

Purva Gopal ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Damage ◽

Genomic Instability ◽

Dna Damage Repair ◽

Strand Break ◽

Damage Repair ◽

Dna End Resection ◽

Non Homologous End Joining ◽

Transformed Cell Lines ◽

Dna Ends

SUMMARYMultiple pathways mediate the repair of DNA double-strand break (DSB), with numerous mechanisms responsible for driving choice between the pathways. Previously, we reported that phosphorylation of the non-homologous end joining (NHEJ) factor, Ku70, is required for the dissociation of the Ku heterodimer from DNA ends to allow DSB repair via homologous recombination (HR). A knock-in mouse, in which phosphorylation is ablated in the three conserved sites of Ku70 (Ku703A/3A), was generated in order to test the hypothesis that Ku70 phosphorylation is required for initiation of HR and that blocking this process results in enhanced genomic instability and tumorigenesis. Here, we show that Ku703A/3A mice develop spontaneous and have accelerated chemical-induced hepatocellular carcinoma (HCC) compared to wild-type (Ku70+/+) littermates. The HCC tumors from the Ku703A/3A mice have increased γH2AX and 8-oxo-G staining, suggesting DNA repair is decreased in these mice. Spontaneous transformed cell lines from Ku703A/3A mice are more radiosensitive, have a significant decrease in DNA end resection, and are more sensitive to the DNA cross-linking agent mitomycin C compared to cells from Ku70+/+ littermates. Collectively, these findings demonstrate that phosphorylation-mediated dissociation of Ku heterodimer from DNA ends is required for efficient DNA damage repair and disruption of this process results in genomic instability and accelerated development of HCC.

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MiR‐320b/RAD21 axis affects hepatocellular carcinoma radiosensitivity to ionizing radiation treatment through DNA damage repair signaling

Cancer Science ◽

10.1111/cas.14751 ◽

2020 ◽

Author(s):

Jianyang Wang ◽

Hong Zhao ◽

Jing Yu ◽

Xin Xu ◽

Hao Jing ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Damage ◽

Ionizing Radiation ◽

Radiation Treatment ◽

Dna Damage Repair ◽

Damage Repair

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Co-targeting WIP1 and PARP induces synthetic lethality in hepatocellular carcinoma

10.21203/rs.3.rs-238597/v1 ◽

2021 ◽

Author(s):

Miaoqin Chen ◽

Weikai Wang ◽

Shiman Hu ◽

Yifan Tong ◽

Yiling Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Damage ◽

Poor Prognosis ◽

Synthetic Lethality ◽

Dna Damage Repair ◽

Gene Set Enrichment Analysis ◽

Parp Inhibition ◽

Damage Repair ◽

Hcc Cells

Abstract BackgroundHepatocellular carcinoma (HCC) is one of the most fatal cancers. Due to limited strategies for effective treatments, patients with advanced HCC have a very poor prognosis. This study aims to identify novel druggable candidate genes for patients with HCC.MethodsThe role of WIP1 (wild type p53 induced protein phosphatase1) in HCC was analyzed in HCC cells, nude mice assay, WIP1 knockout mice, and TCGA database. DNA damage was evaluated by Gene Set Enrichment Analysis, Western blotting, comet assay, and Immunofluorescence.ResultsHigh expression of WIP1 is associated with poor prognosis of patients with HCC. Genetically and chemically suppression of WIP1 drastically reduced HCC cell proliferation in vitro and in vivo via inducing DNA damage. WIP1 knockout retarded DEN (Diethylnitrosamine) induced mice hepato-carcinogenesis. In addition, suppression of WIP1 together with PARP inhibition induced synthetic lethality in HCC cells by disrupting DNA damage repair.ConclusionWIP1 plays an oncogenic effect in HCC development, and targeting WIP1-dependent DNA damage repair might be a novel strategy for HCC management.

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PARP inhibitor Olaparib overcomes Sorafenib resistance through reshaping the pluripotent transcriptome in hepatocellular carcinoma

Molecular Cancer ◽

10.1186/s12943-021-01315-9 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Xiao-Dong Yang ◽

Fan-En Kong ◽

Ling Qi ◽

Jia-Xin Lin ◽

Qian Yan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Damage ◽

Stem Cell ◽

Parp Inhibitor ◽

Dna Damage Repair ◽

Embryonic Stem ◽

Hepatic Differentiation ◽

Sorafenib Treatment ◽

Damage Repair ◽

Stem Cell Pluripotency

AbstractHepatocellular carcinoma (HCC) is one of the most common human malignancies worldwide with very poor prognosis. Resistance to targeted therapeutic drugs such as sorafenib remains one of the major challenges in clinical treatment. In the present study, PARP1 was found to be highly expressed in human embryonic stem cells, but progressively decreased upon specified hepatic differentiation. Reactivation of PARP1 expression was also detected in HCC residual tumors after sorafenib treatment in xenograft mouse model, indicating the potential important roles of PARP1 in stem cell pluripotency and HCC sorafenib treatment resistance. Overexpression of PARP1 was frequently observed in HCC patients, and closely associated with poor clinical outcome. Treatment of Sorafenib induced activation of DNA damage repair signaling, which is highly active and essential for maintenance of stem cell pluripotency in HCC residual tumors. PARP inhibitor Olaparib extensively suppressed the DNA damage repair signaling, and significantly inhibited the global pluripotent transcriptional network. The repression of key pluripotent transcriptional factors and DNA damage repair signaling by Olaparib was mainly through CHD1L-mediated condensation of the chromatin structure at their promotor regions. The global reshaping of the pluripotent transcriptome by Olaparib might reinforce Sorafenib in eliminating HCC residual tumors and enhance therapeutic efficiency.

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Proteomic Identification of a Direct Role for Cyclin D1 in DNA Damage Repair: Figure 1.

Cancer Research ◽

10.1158/0008-5472.can-11-3549 ◽

2012 ◽

Vol 72 (17) ◽

pp. 4289-4293 ◽

Cited By ~ 50

Author(s):

Siwanon Jirawatnotai ◽

Yiduo Hu ◽

David M. Livingston ◽

Piotr Sicinski

Keyword(s):

Dna Damage ◽

Cyclin D1 ◽

Dna Damage Repair ◽

Direct Role ◽

Damage Repair ◽

Proteomic Identification

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DNA Damage Repair Profiles Alteration Characterize a Hepatocellular Carcinoma Subtype With Unique Molecular and Clinicopathologic Features

Frontiers in Immunology ◽

10.3389/fimmu.2021.715460 ◽

2021 ◽

Vol 12 ◽

Author(s):

Peng Lin ◽

Rui-zhi Gao ◽

Rong Wen ◽

Yun He ◽

Hong Yang

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Damage ◽

Molecular Mechanisms ◽

Dna Damage Repair ◽

Clinicopathological Features ◽

Molecular Characteristics ◽

Molecular Features ◽

Damage Repair ◽

Molecular Phenotypes ◽

Aggressive Clinical Behavior

Hepatocellular carcinoma (HCC) is one of the most common malignancies and displays high heterogeneity of molecular phenotypes. We investigated DNA damage repair (DDR) alterations in HCC by integrating multi-omics data. HCC patients were classified into two heterogeneous subtypes with distinct clinical and molecular features: the DDR-activated subtype and the DDR-suppressed subtype. The DDR-activated subgroup is characterized by inferior prognosis and clinicopathological features that result in aggressive clinical behavior. Tumors of the DDR-suppressed class, which have distinct clinical and molecular characteristics, tend to have superior survival. A DDR subtype signature was ultimately generated to enable HCC DDR classification, and the results were confirmed by using multi-layer date cohorts. Furthermore, immune profiles and immunotherapy responses are also different between the two DDR subtypes. Altogether, this study illustrates the DDR heterogeneity of HCCs and is helpful to the understanding of personalized clinicopathological and molecular mechanisms responsible for unique tumor DDR profiles.

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Abstract 2040: Analysis of DNA damage repair gene alterations and their association with tumor mutation burden in 1427 hepatocellular carcinoma patients

10.1158/1538-7445.am2021-2040 ◽

2021 ◽

Author(s):

Mengmei Yang ◽

Wenzhuan Xie ◽

Mengli Huang ◽

Xinhua Zhu

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Damage ◽

Dna Damage Repair ◽

Repair Gene ◽

Tumor Mutation Burden ◽

Damage Repair ◽

Mutation Burden ◽

Gene Alterations

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Cyclin D1 Integrates Estrogen-Mediated DNA Damage Repair Signaling

Cancer Research ◽

10.1158/0008-5472.can-13-3137 ◽

2014 ◽

Vol 74 (14) ◽

pp. 3959-3970 ◽

Cited By ~ 23

Author(s):

Zhiping Li ◽

Ke Chen ◽

Xuanmao Jiao ◽

Chenguang Wang ◽

Nicole E. Willmarth ◽

...

Keyword(s):

Dna Damage ◽

Cyclin D1 ◽

Dna Damage Repair ◽

Damage Repair

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DNA Damage Repair Status Predicts Opposite Clinical Prognosis Immunotherapy and Non-Immunotherapy in Hepatocellular Carcinoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.676922 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yunfei Chen ◽

Xu Wang ◽

Xiaofan Deng ◽

Yu Zhang ◽

Rui Liao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Damage ◽

Immune Cells ◽

Immune Checkpoint ◽

Dna Damage Repair ◽

Objective Response ◽

Traditional Treatment ◽

Clinical Prognosis ◽

Damage Repair ◽

Potential Biomarker

Immune checkpoint inhibitors(ICIs) that activate tumor-specific immune responses bring new hope for the treatment of hepatocellular carcinoma(HCC). However, there are still some problems, such as uncertain curative effects and low objective response rates, which limit the curative effect of immunotherapy. Therefore, it is an urgent problem to guide the use of ICIs in HCC based on molecular typing. We downloaded the The Cancer Genome Atlas-Liver hepatocellular carcinoma(TCGA-LIHC) and Mongolian-LIHC cohort. Unsupervised clustering was applied to the highly variable data regarding expression of DNA damage repair(DDR). The CIBERSORT was used to evaluate the proportions of immune cells. The connectivity map(CMap) and pRRophetic algorithms were used to predict the drug sensitivity. There were significant differences in DDR molecular subclasses in HCC(DDR1 and DDR2), and DDR1 patients had low expression of DDR-related genes, while DDR2 patients had high expression of DDR-related genes. Of the patients who received traditional treatment, DDR2 patients had significantly worse overall survival(OS) than DDR1 patients. In contrast, of the patients who received ICIs, DDR2 patients had significantly prolonged OS compared with DDR1 patients. Of the patients who received traditional treatment, patients with high DDR scores had worse OS than those with low DDR scores. However, the survival of patients with high DDR scores after receiving ICIs was significantly higher than that of patients with low DDR scores. The DDR scores of patients in the DDR2 group were significantly higher than those of patients in the DDR1 group. The tumor microenvironment(TME) of DDR2 patients was highly infiltrated by activated immune cells, immune checkpoint molecules and proinflammatory molecules and antigen presentation-related molecules. In this study, HCC patients were divided into the DDR1 and DDR2 group. Moreover, DDR status may serve as a potential biomarker to predict opposite clinical prognosis immunotherapy and non-immunotherapy in HCC.

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