Clinical values of Ku80 upregulation in superficial esophageal squamous cell carcinoma

Wang, Shuai; Xi, Junjie; Zhang, Lin; Hao, Jiatao; Yao, Cheng‐Bao; Zhan, Cheng; Jiang, Wei; Shi, Yu; Wang, Qun

doi:10.1002/cam4.1314

Cited by 4 publications

(3 citation statements)

References 39 publications

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“…In hepatocellular carcinoma, overexpression of Ku80 is shown to lead to metastasis [ 30 ]. Notably, in patients with superficial esophageal squamous cell carcinoma, overexpression of Ku80 led to poor prognosis [ 31 ]. Furthermore, in Ku-deficient cells, PCNA dissociates from the chromosome and Ku is required to maintain PCNA on the chromosome [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Interception of Signaling Circuits of Esophageal Adenocarcinoma Cells by Resveratrol Reveals Molecular and Immunomodulatory Signatures

Dhir

Choudhury

Patil

et al. 2021

Cancers

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Deregulation of signaling pathways due to mutations sets the cell on a path to neoplasia. Therefore, recent reports of increased mutations observed in esophageal tissue reflects the enhanced risk of tumor formation. In fact, adenocarcinoma of the esophagus has been on the rise lately. Increase in mortality due to a paucity of efficacious drugs for this cancer prompted us to discover molecular signatures to combat this malady. To this end, we chose resveratrol—a polyphenol with anticancer property—and studied its impact on three esophageal adenocarcinoma cell lines (OE33, OE19 and FLO-1) by multilevel profiling. Here, we show the impact of resveratrol on the viability of the three adenocarcinoma esophageal cell systems studied, at the cellular level. Furthermore, an analysis at the molecular level revealed that the action was through the programmed cell death pathway, resulting in an increase in apoptotic and caspase-positive cells. The impact on reactive oxygen species (ROS) and a decrease in Bcl2 levels were also observed. Moreover, proteomic profiling highlighted pivotal differentially regulated signaling molecules. The phenotypic effect observed in resveratrol-treated esophageal cells could be due to the stoichiometry per se of the fold changes observed in entities of key signaling pathways. Notably, the downregulation of Ku80 and other pivotal entities by resveratrol could be harnessed for chemo-radiation therapy to prevent DNA break repair after radiation therapy. Additionally, multilevel profiling has shed light on molecular and immune-modulatory signatures with implications for discovering novel treatments, including chemo-immunotherapy, for esophageal adenocarcinomas which are known to be aggressive cancers.

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Section: Discussionmentioning

confidence: 99%

Interception of Signaling Circuits of Esophageal Adenocarcinoma Cells by Resveratrol Reveals Molecular and Immunomodulatory Signatures

Dhir

Choudhury

Patil

et al. 2021

Cancers

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“…To date, only infrequent rate of mutations of XRCC6 or XRCC5 (0.96 and 1.1% of AACR GENIE cases, respectively), has been reported ( AACR Project Genie Consortium, 2017 ; Printz, 2017 ). Yet, Ku has been found frequently dysregulated in tumors ( Komuro et al, 2002 ; Mazzarelli et al, 2005 ; Korabiowska et al, 2006 ; Abdelbaqi et al, 2013 ; Wang et al, 2015 , 2018 ; Zhu et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Deficiency of Ku Induces Host Cell Exploitation in Human Cancer Cells

Saydam

2021

Front. Cell Dev. Biol.

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Cancer metastasis is the major cause of death from cancer (Massague and Obenauf, 2016; Steeg, 2016). The extensive genetic heterogeneity and cellular plasticity of metastatic tumors set a prime barrier for the current cancer treatment protocols (Boumahdi and de Sauvage, 2020). In addition, acquired therapy resistance has become an insurmountable obstacle that abolishes the beneficial effects of numerous anti-cancer regimens (De Angelis et al., 2019; Boumahdi and de Sauvage, 2020). Here we report that deficiency of Ku leads to the exploitation of host cells in human cancer cell line models. We found that, upon conditional deletion of XRCC6 that codes for Ku70, HCT116 human colorectal cancer cells gain a parasitic lifestyle that is characterized by the continuous cycle of host cell exploitation. We also found that DAOY cells, a human medulloblastoma cell line, innately lack nuclear Ku70/Ku86 proteins and utilize the host-cell invasion/exit mechanism for maintenance of their survival, similarly to the Ku70 conditionally-null HCT116 cells. Our study demonstrates that a functional loss of Ku protein promotes an adaptive, opportunistic switch to a parasitic lifestyle in human cancer cells, providing evidence for a previously unknown mechanism of cell survival in response to severe genomic stress. We anticipate that our study will bring a new perspective for understanding the mechanisms of cancer cell evolution, leading to a shift in the current concepts of cancer therapy protocols directed to the prevention of cancer metastasis and therapy resistance.

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“…The downregulation of period circadian regulator 1 ( PER1 ) gene expression has been found to enhance tumorigenicity and proliferation of oral squamous cell carcinoma cells [ 39 ]. Furthermore, inhibited expression of X-ray repair cross-complementing 5 ( XRCC5 ) in ESCC cells has been linked to reduced malignancies of tumor cells, such as proliferation, clonal progression, and apoptosis escape [ 40 ]. Besides, our GSEA results also showed significant enrichment of genes involved in cell cycle and mitotic spindle regulations in the low DRGS group and those involved in metabolic process-related pathways in the high DRGS group.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Ten-Gene Signature of DNA Damage Response Pathways with Prognostic Value in Esophageal Squamous Cell Carcinoma

Zhuang

Ben

Zhou

et al. 2021

Journal of Oncology

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Molecular prognostic signatures are critical for treatment decision-making in esophageal squamous cell cancer (ESCC), but the robustness of these signatures is limited. The aberrant DNA damage response (DDR) pathway may lead to the accumulation of mutations and thus accelerate tumor progression in ESCC. Given this, we applied the LASSO Cox regression to the transcriptomic data of DDR genes, and a prognostic DDR-related gene expression signature (DRGS) consisting of ten genes was constructed, including PARP3, POLB, XRCC5, MLH1, DMC1, GTF2H3, PER1, SMC5, TCEA1, and HERC2. The DRGS was independently associated with overall survival in both training and validation cohorts. The DRGS achieved higher accuracy than six previously reported multigene signatures for the prediction of prognosis in comparable cohorts. Furtherly, a nomogram incorporating DRGS and clinicopathological features showed improved predicting performance. Taken together, the DRGS was identified as a novel, robust, and effective prognostic indicator, which may refine the scheme of risk stratification and management in ESCC patients.

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Clinical values of Ku80 upregulation in superficial esophageal squamous cell carcinoma

Cited by 4 publications

References 39 publications

Interception of Signaling Circuits of Esophageal Adenocarcinoma Cells by Resveratrol Reveals Molecular and Immunomodulatory Signatures

Interception of Signaling Circuits of Esophageal Adenocarcinoma Cells by Resveratrol Reveals Molecular and Immunomodulatory Signatures

Deficiency of Ku Induces Host Cell Exploitation in Human Cancer Cells

Identification of a Ten-Gene Signature of DNA Damage Response Pathways with Prognostic Value in Esophageal Squamous Cell Carcinoma

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