Targeting HMGB3/hTERT axis for radioresistance in cervical cancer

Li, Zongjuan; Zhang, Yang; Sui, Silei; Hua, Yi-Jun; Zhao, Anshi; Tian, Xiaoyuan; Wang, Ruonan; Guo, Wei; Yu, Wei; Zou, Kun; Deng, Wuguo; He, Liru; Zou, Lijuan

doi:10.1186/s13046-020-01737-1

Cited by 34 publications

(25 citation statements)

References 50 publications

(58 reference statements)

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“…Silencing of GRP94 in CC cells induced increased sensitivity to radiotherapy [27]. Besides, Zou found that depletion of HMGB3 signi cantly enhanced the radio-sensitivity of CC cells, while overexpression of HMGB3 had the opposite effect; this effect was mediated via transcriptional upregulation of hTERT [28]. The present study found a correlation between high level of HNF1α and radio-resistance of CC tissues.…”

Section: Discussionsupporting

confidence: 62%

HNF1α Contributes to Radio-Resistance in Cervical Cancer Via Regulating the CircHNF1α/miR-204-3p/RAD51D Regulatory Axis

Du¹,

Zou²,

Zuo³

et al. 2020

Preprint

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Background: Radiotherapy as an important primary treatment has effectively improved the survival of patients with cervical cancer (CC). However, some patients do not show optimal benefits of radiotherapy due to radio-resistance. Therefore, identification of biomarkers of radio-resistance and unraveling the underlying mechanisms of radio-resistance is a key imperative for these patients.Methods: The expression levels of circHNF1α, miRNAs, and mRNA in tissues and cell lines were detect by qRT-PCR analysis. The levels of proteins were analyzed by western blot. Cell proliferation ability was measured by colony formation assay. RNA pull-down and uciferase reporter assay analysis were performed to identify the sponging microRNAs of circHNF1α. The target gene of miR-204-3p was determined by luciferase reporter assay. Chromatin immunoprecipitation (ChIP) analysis and luciferase reporter assay were performed to identify the transcription factor of circHNF1α. Results: We found significant upregulation of HNF1α expression in radio-resistant cervical cancer tissues and cell lines. Depletion of HNF1α reduced whereas overexpression of HNF1α promoted the resistance of CC cells to irradiation in vitro and in vivo. HNF1α positively regulated RAD51D at the protein level but not at the mRNA level, thus attenuating radio-resistance of CC cells. Mechanistically, upregulation of HNF1α enhanced circHNF1α transcription and promoted circHNF1α biogenesis, which in turn sponged miR-204-3p and thus relieved their repression of the RAD51D expression. The HFN1α/circHNF1α/miR-204-3p/RAD51D regulatory axis was found to play a critical role in conferring radio-resistance of CC cells.Conclusions: Dysregulation of the HFN1α/circHNF1α/miR-204-3p/RAD51D axis may promote the radio-resistance of CC cells. Blocking this pathway may provide therapeutic benefits against CC radio-resistance.

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Section: Discussionsupporting

confidence: 62%

HNF1α Contributes to Radio-Resistance in Cervical Cancer Via Regulating the CircHNF1α/miR-204-3p/RAD51D Regulatory Axis

Du¹,

Zou²,

Zuo³

et al. 2020

Preprint

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show abstract

“…Notably, HMGB3 is highly expressed and plays a vital role in the malignant progression of a variety of cancers [ 8 ]. Overexpressed HMGB3 is closely related to tumor occurrence and reduced survival in cervical cancer [ 12 ], non-small-cell lung cancer [ 13 ], breast cancer [ 14 ], bladder cancer [ 15 ], hepatocellular carcinoma [ 16 ], colorectal cancer [ 17 ], gastric cancer [ 18 ], and leukemia [ 19 , 20 ]. However, the expression pattern and clinicopathological characteristics of HMGB3 in high-grade serous ovarian carcinoma (HGSOC) have not been reported.…”

Section: Introductionmentioning

confidence: 99%

“…HMGB3 also participates in the regulation of chemotherapy resistance for several tumors. Li et al observed that HMGB3 transcriptionally activates human telomerase reverse transcriptase (hTERT) and promotes the DNA damage response, contributing to the development of radioresistance in cervical cancer [ 12 ]. HMGB3 has been revealed to be targeted by miR-27b and is associated with tamoxifen resistance in breast cancer [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

HMGB3 promotes PARP inhibitor resistance through interacting with PARP1 in ovarian cancer

Han

et al. 2022

Cell Death Dis

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Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) resistance remains a therapeutic challenge in ovarian cancer. High-mobility group box 3 (HMGB3) plays significant roles in the development of drug resistance of many cancers. However, the function of HMGB3 in PARPi resistance is poorly understood. In the current study, we clarified that HMGB3 was aberrantly overexpressed in high-grade serous ovarian carcinoma (HGSOC) tissues, and high HMGB3 levels indicated shorter overall survival and drug resistance in HGSOC. The overexpression of HMGB3 increased the insensitivity of ovarian cancer to PARPi, whereas HMGB3 knockdown reduced PARPi resistance. Mechanistically, PARP1 was identified as a novel interaction partner of HMGB3, which could be blocked using olaparib and was enhanced upon DNA damage conditions. We further showed that loss of HMGB3 induced PARP1 trapping at DNA lesions and inhibited the PARylation activity of PARP1, resulting in an increased DNA damage response and cell apoptosis. The PARPi-resistant role of HMGB3 was also verified in a xenograft mouse model. In conclusion, HMGB3 promoted PARPi resistance via interacting with PARP1, and the targeted inhibition of HMGB3 might overcome PARPi resistance in ovarian cancer therapy.

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“…Loss of CIRBP expression is correlated with the malignant progression and poor prognosis in nasopharyngeal carcinoma [29]. Among the 11 coding genes, HMGB3 was widely reported to promote malignant progress and predict poor survival in various cancer types [30][31][32]. In addition, Gu et al reported that HMGB3 silence could inhibit the cell proliferation in vitro and suppress tumor growth in vivo levels.…”

Section: Discussionmentioning

confidence: 99%

Construction and validation of a prognostic model based on 11 lymph node metastasis‐related genes for overall survival in endometrial cancer

Feng

Miao

et al. 2022

Cancer Medicine

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Background: Endometrial cancer (EC) is one of the most common malignant tumor in the female reproductive system. The incidence of lymph node metastasis (LNM) is only about 10% in clinically suspected early-stage EC patients. Discovering prognostic model and effective biomarkers for early diagnosis is important to reduce the mortality rate.Methods: We downloaded the RNA-sequencing data and clinical information from the TCGA database. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to analyze the differentially expressed genes (DEGs). A least absolute shrinkage and selection operator (LASSO) regression was conducted to identify the characteristic dimension decrease and distinguish prognosis-related LNM related genes signature. Subsequently, a novel prognosis-related nomogram to predict overall survival (OS). A survival analysis was carried out to explore the individual prognostic signi cance of the risk model and key gene was validated in vitro.Results: In total, 89 LRGs were identi ed. Based on the LASSO Cox regression, 11 genes were selected for the development of a risk evaluation model. The Kaplan-Meier curve indicated that patients in the lowrisk group had considerably better OS (P = 3.583e−08). The area under the curve (AUC) of this model was 0.718 at 5 years of OS. Then, we developed an OS-associated nomogram that included the risk score and clinicopathological features. The concordance index of the nomogram was 0.769. The survival veri cation performed in three subgroups from the nomogram demonstrated the validity of the model.The AUC of the nomogram was 0.787 at 5 years OS. Proliferation and metastasis of HMGB3 were explored in EC cell line. Finally, we revealed that the most frequently mutated genes in the low-risk and high-risk groups are PTEN and TP53, respectively. Conclusions: Our results suggest that LNM plays an important role in the prognosis, and HMGB3 was potential as a biomarker for EC patients. By detecting the mutation of the risk signature, clinicians can accurately treat patients with targeted therapy, thereby improving their survival rate.

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Targeting HMGB3/hTERT axis for radioresistance in cervical cancer

Cited by 34 publications

References 50 publications

HNF1α Contributes to Radio-Resistance in Cervical Cancer Via Regulating the CircHNF1α/miR-204-3p/RAD51D Regulatory Axis

HNF1α Contributes to Radio-Resistance in Cervical Cancer Via Regulating the CircHNF1α/miR-204-3p/RAD51D Regulatory Axis

HMGB3 promotes PARP inhibitor resistance through interacting with PARP1 in ovarian cancer

Construction and validation of a prognostic model based on 11 lymph node metastasis‐related genes for overall survival in endometrial cancer

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