Wnt signaling induces radioresistance through upregulating HMGB1 in esophageal squamous cell carcinoma

Zhao, Yuanyuan; Yi, Jun; Tao, Leilei; Huang, Guichun; Chen, Xiaoyuan; Song, Haiyan; Chen, Longbang

doi:10.1038/s41419-018-0466-4

Cited by 54 publications

(41 citation statements)

References 37 publications

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“…Activation of Wnt signaling is also one of the mechanisms that promotes radioresistance in cancers such as glioblastoma, colorectal, esophageal and nasopharyngeal cancers. This was mainly attributed to the ability of Wnts in promoting 430 cellular proliferation and maintenance of stem cells (12)(13)(14)80). Our study suggests that activation of Wnt signaling in these cancers may enhance their ability to repair DNA damage and hence induce resistance and maintenance of stem cells.…”

Section: Discussionmentioning

confidence: 73%

“…Wnt signaling is important for the maintenance of stem cell state, adult tissue homeostasis and the prevention of differentiation (10). Wnt signaling is also associated with the development of radioresistance in many cancers but the underlying mechanisms are not well understood (11)(12)(13)(14)(15)(16). Wnts are a family of 19 secreted palmitoleated 70 glycoproteins that signal by binding to Frizzled (FZD) and additional co-receptors on the cell surface.…”

Section: Introductionmentioning

confidence: 99%

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WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

Kaur

Sepramaniam

Lim

et al. 2020

Preprint

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Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have 30 proven effective in Wnt-addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt-addicted cancers. Mechanistically, we find that multiple genes in the homologous recombination and Fanconi anemia repair pathways, including BRCA1, FANCD2, and RAD51 are dependent on Wnt/β-catenin signaling in Wnt-high cancers, and treatment with a PORCN inhibitor creates a BRCA-like state. This coherent regulation of DNA repair genes occurs via a Wnt/β-catenin/MYBL2 axis. Importantly, this pathway also functions in intestinal crypts, where high expression of BRCA and Fanconi anemia genes is seen in intestinal stem cells, with further upregulation in Wnt high APC min mutant polyps. Our findings suggest a general paradigm that Wnt/β-40 catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents. 610

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Section: Discussionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

Kaur

Sepramaniam

Lim

et al. 2020

Preprint

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“…Radiotherapy is extensively used for the treatment of advanced malignant tumors, including EScc (32,33). Nevertheless, the radioresistance of EScc cells, which is caused by a series of factors, can result in treatment failure (34).…”

Section: Discussionmentioning

confidence: 99%

LINC00473 contributes to the radioresistance of esophageal squamous cell carcinoma by regulating microRNA‑497‑5p and cell division cycle 25A

Liu

Qiao

et al. 2020

Int J Mol Med

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Long non-coding RNA (lncRNA) LINc00473 plays a carcinogenic role in a variety of different tumor types. Nevertheless, the mechanisms through which LINc00473 regulates the radiosensitivity of esophageal squamous cell carcinoma (EScc) cells remains elusive. In the present study, reverse transcription-quantitative PcR was used to quantify the expression of LINc00473, microRNA (miRNA/miR)-497-5p and cell division cycle 25A (cdc25A) in EScc tissues. The association between LINc00473 expression and the clinicopathological characteristics of patients with EScc was also assessed. Furthermore, cell counting kit-8 and colony formation assays were carried out to monitor the proliferation of EScc cells exposed to X-ray radiation. A dual-luciferase reporter assay was also conducted to analyze the interaction between LINc00473 and miR-497-5p, as well as the interaction between CDC25A and miR-497-5p. The findings of the present study demonstrated that in EScc tissues and cells, the expression levels of LINC00473 and CDC25A were significantly upregulated, while the expression of miR-497-5p was downregulated. The high expression level of LINc00473 was associated with a higher T stage, lymph node metastasis stage and a lower tumor differentiation grade in patients with EScc. Following irradiation, transfection with miR-497-5p mimics reduced the promoting effect of LINc00473 overexpression on EScc cell proliferation, and partially impeded the resistance of EScc cells to X-ray radiation induced by LINc00473 overexpression. Moreover, transfection with miR-497-5p inhibitors partially alleviated the inhibitory effects of LINc00473 knockdown on cellular proliferation, and partly reversed the sensitivity of cells to X-ray irradiation induced by LINc00473 knockdown. Furthermore, it was confirmed that miR-497-5p was able to bind LINc00473 and the 3'-untranslated region of CDC25A. On the whole, the findings of the present study demonstrate that LINc00473 reduces the radiosensitivity of EScc cells by modulating the miR-497-5p/cdc25A axis.

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“…Wnt3 is also reported to be associated with the tumorigenicity and poor prognosis of ESCC [22,23]. Importantly, Wnt-β-catenin signaling is found to enhance radioresistance of ESCC [24]. Bioinformatics softwares predicted there are binding sites between miR-217 and Wnt3 3'UTR.…”

Section: Introductionmentioning

confidence: 99%

CircRNA_100367 regulated the radiation sensitivity of esophageal squamous cell carcinomas through miR-217/Wnt3 pathway

Liu

Xue

Guo

et al. 2019

Aging

121

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Background: Circular RNAs (circRNAs) play important roles in regulating the radioresistance of esophageal squamous cell carcinoma (ESCC). This study aimed to determine the role of hsa_circRNA_100367 in regulating radioresistance of ESCC. Results: Higher expression and potency of endothelial to mesenchymal transformation (EMT) was found in radioresistant ESCC cells (KYSE-150R) than in ESCC cells (KYSE-150). Silencing circRNA_100367 inhibited the proliferation and migration of KYSE-150R cells, and decreased the expression of β-catenin (an important molecule in Wnt pathway) in KYSE-150R cells. Additionally, circRNA_100367 bound to miR-217, and miR-217 targeted Wnt3. Low Wnt3 expression was associated with the short survival time in patients with ESCC and Wnt3 knockdown inhibited the proliferation and migration of KYSE-150R cells. CircRNA_100367 enhanced the radioresistance of KYSE-150R cells through miR-217/Wnt3 pathway. In vivo, circRNA_100367 silence reduced the growth of KYSE-150R cells under radiation. Conclusion: Our results revealed that circRNA_100367 attenuated radioresistance of ESCC through miR-217/Wnt3 pathway. Methods: CircRNAs related with the radioresistance of ESCC were analyzed by hierarchical cluster analysis. The relationship between circRNA_100367 and miR-217, Wnt3 was detected by RNA immunoprecipitation (RIP), RNA pull-down and luciferase reporte assays. The proliferation and migration ESCC cells were detected by MTT, Transwell and colony formation assays.

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Wnt signaling induces radioresistance through upregulating HMGB1 in esophageal squamous cell carcinoma

Cited by 54 publications

References 37 publications

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

LINC00473 contributes to the radioresistance of esophageal squamous cell carcinoma by regulating microRNA‑497‑5p and cell division cycle 25A

CircRNA_100367 regulated the radiation sensitivity of esophageal squamous cell carcinomas through miR-217/Wnt3 pathway

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