Wnt signaling induces radioresistance through upregulating HMGB1 in esophageal squamous cell carcinoma.
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ABSTRACT:
SUBMITTER: Zhao Y
PROVIDER: S-EPMC5864958 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In the tumor microenvironment, inflammatory cells and molecules influence almost every process; among them, interleukin-23 (IL-23) is a pro-inflammatory molecule that exhibits pro- or anti-tumor properties, but both activities remain poorly understood. In this study, we investigated the effect of extracellular IL-23 in IL-23 receptor-positive (IL-23R+) esophageal squamous cell carcinoma (ESCC) and explored the mechanisms underlying this effect. We analyzed ESCC tumor tissues by immunohistochemical and immunofluorescence staining and found that IL-23, which was highly expressed, co-localized with Oct-4A in IL-23R+ ESCC cells. In addition, IL-23 treatment significantly increased the accumulation of CD133+ cells and activated the Wnt and Notch signaling pathways in CD133-IL-23R+ ESCC cell lines. Consistently, CD133-IL-23R+ cells pretreated with IL-23 showed stronger anti-apoptosis activity when exposed to radiation and higher survival than untreated groups. Moreover, the inhibition of Wnt/Notch signaling by a small-molecule inhibitor or siRNA abolished the effect of IL-23-induced dormancy and consequent radioresistance. Taken together, these results suggested that IL-23 facilitates radioresistance in ESCC by activating Wnt/Notch-mediated G0/1 phase arrest, and attenuating these detrimental changes by blocking the formation of dormancy may prove to be an effective pretreatment for radiotherapy. KEY MESSAGES: IL-23/IL-23R is correlated with the acquisition of stem-like potential in ESCC. CD133-IL-23R+ ESCCs acquired dormancy via IL-23. Radioresistance depends on IL-23-mediated Wnt/Notch pathway activation in vitro and vivo.
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Project description:BACKGROUND:Capn4 and ZEB1 play important roles in the metastasis of several types of cancer. However, the roles and relationship of Capn4 and ZEB1 in esophageal squamous cell carcinoma (ESCC) remain unclear. METHODS:ESCC tumor tissues and corresponding normal esophageal epithelial tissues were obtained from 86 patients undergoing resection surgery at the Department of General Surgery, First Affiliated Hospital of Chinese PLA General Hospital from 2012 to 2017. Cell migration and invasion were examined via quantitative real-time PCR and Western blot assay. RESULTS:Our results indicate that both Capn4 and ZEB1 are significantly upregulated in ESCC tissues compared to corresponding adjacent tissues, and a positive correlation between expression and associated malignant characteristics was found. Silencing of Capn4 expression markedly inhibited ESCC invasion and metastasis in vitro and in vivo, and was accompanied by decreased ZEB1 expression. Furthermore, the anti-metastasis role of Capn4 silencing was reversed by ZEB1 overexpression, whereas knockdown of ZEB1 decreased ESCC metastasis driven by the upregulation of Capn4. Mechanistically, Capn4 regulated ZEB1 expression via activation of the Wnt/?-catenin signaling pathway in ESCC cells. CONCLUSION:Overall, our results show that enhanced Capn4 expression activates the Wnt/?-catenin signaling pathway, resulting in increased ZEB1 expression and the promotion of ESCC cell metastasis.
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Project description:N-myc down-regulated gene 1 (NDRG1) has been shown to regulate tumor growth and metastasis in various malignant tumors and also to be dysregulated in esophageal squamous cell carcinoma (ESCC). Here, we show that NDRG1 overexpression (91.9%, 79/86) in ESCC tumor tissues is associated with poor overall survival of esophageal cancer patients. When placed in stable transfectants of the KYSE 30 ESCC cell line generated by lentiviral transduction with the ectopic overexpression of NDRG1, the expression of transducin-like enhancer of Split 2 (TLE2) was decreased sharply, however ?-catenin was increased. Mechanistically, NDRG1 physically associates with TLE2 and ?-catenin to affect the Wnt pathway. RNA interference and TLE2 overexpression studies demonstrate that NDRG1 fails to active Wnt pathway compared with isogenic wild-type controls. Strikingly, NDRG1 overexpression induces the epithelial mesenchymal transition (EMT) through activating the Wnt signaling pathway in ESCC cells, decreased the expression of E-cadherin and enhanced the expression of Snail. Our study elucidates a mechanism of NDRG1-regulated Wnt pathway activation and EMT via affecting TLE2 and ?-catenin expression in esophageal cancer cells. This indicates a pro-oncogenic role for NDRG1 in esophageal cancer cells whereby it modulates tumor progression.
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Project description:Objective:To explore the regulation of long-chain noncoding BANCR on cell invasion and migration of esophageal squamous carcinoma cells and related mechanisms. Method:The mRNA expression of BANCR in esophageal squamous carcinoma cells and esophageal squamous cells was detected by quantitative PCR . The relationship between the expression of BANCR and the survival rate of patients with esophageal squamous cell carcinoma (ESCC) was analyzed by Kaplan-Meier method. The BANCR pair was detected by Transwell invasion and scratch test. In ESCC cell lines, the cells had invasion and migration ability; Western blot was applied to detect the expression of proteins involved in the Wnt/?-catenin signaling pathway. Results:BANCR revealed relatively high expression in esophageal squamous carcinoma cells, and the higher the expression of BANCR was, the lower the survival rate of patients with ESCC was. Inhibition of BANCR expression could effectively reduce the invasion and migration ability of esophageal squamous cell carcinoma. After silencing BANCR, the expression of wnt3a, survivin, ?-catenin and c-myc protein was downregulated compared with the negative control group (p<0.05). Conclusion:Long-chain noncoding BANCR was highly expressed in patients with ESCC and was negatively correlated with patients' survival time. It was of the capability to modulate the cell migration and invasion of ESCC cells through inducing Wnt/?-catenin signaling pathway.
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Project description:TP53 is associated with the resistance of cytotoxic treatment and patient prognosis, and the mutation rate of TP53 in esophageal squamous cell carcinoma (ESCC) is extraordinarily high, at over 90%. PRIMA-1 (p53 re-activation and induction of massive apoptosis) has recently been reported to restore the function of mutant TP53; however, its antitumor effect and mechanism in ESCC remain unclear. After evaluating the TP53 mutation status of a panel of 11 ESCC cell lines by Sanger sequencing, we assessed the in vitro effect of PRIMA-1 administration on cells with different TP53 status by conducting cell viability and apoptosis assays. The expression levels of proteins in p53-related pathways were examined by Western blotting, while knockdown studies were conducted to investigate the mechanism underlying PRIMA-1's function. An ESCC xenograft model was further used to evaluate the therapeutic effect of PRIMA-1 in vivo. PRIMA-1 markedly inhibited cell growth and induced apoptosis by upregulating Noxa expression in ESCC cell lines with TP53 missense mutations, whereas no apoptosis was induced in ESCC with wild-type TP53 and TP53 with frameshift and nonsense mutations. Importantly, the knockdown of Noxa canceled the apoptosis induced by PRIMA treatment in ESCC cell lines with TP53 missense mutations. PRIMA-1 administration, compared with placebo, showed a significant antitumor effect by inducing Noxa in the xenograft model of an ESCC cell line with a TP53 missense mutation. PRIMA-1 exhibits a significant antitumor effect, inducing massive apoptosis through the upregulation of Noxa in ESCC with TP53 missense mutations.
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Project description:Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly resistant to current treatments. ESCC harbors a subpopulation of cells exhibiting cancer stem-like cell (CSC) properties that contribute to therapeutic resistance including radioresistance, but the molecular mechanisms in ESCC CSCs are currently unknown. Here, we report that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting CSC properties and radioresistance in ESCC. RSK4 was highly expressed in ESCC CSCs and associated with radioresistance and poor survival in patients with ESCC. RSK4 was found to be a direct downstream transcriptional target of ΔNp63α, the main p63 isoform, which is frequently amplified in ESCC. RSK4 activated the β-catenin signaling pathway through direct phosphorylation of GSK-3β at Ser9. Pharmacologic inhibition of RSK4 effectively reduced CSC properties and improved radiosensitivity in both nude mouse and patient-derived xenograft models. Collectively, our results strongly suggest that the ΔNp63α/RSK4/GSK-3β axis plays a key role in driving CSC properties and radioresistance in ESCC, indicating that RSK4 is a promising therapeutic target for ESCC treatment.
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Project description:Ras‑associated protein 1A (Rap1A) is a member of the Ras subfamily of small GTP‑binding proteins and is found to promote metastasis in several types of cancer. However, the functional role and molecular mechanism of action in Rap1A in esophageal squamous cell carcinoma (ESCC) is not fully understood. In the present study, Rap1A was found to be upregulated in ESCC tissues and its expression was correlated with cancer stage. Functional studies revealed that Rap1A could promote ESCC metastasis by stimulating cell migration and invasion in vivo and in vitro. Further study indicated that the transcriptional factor SP1 increased Rap1A expression via promoter binding and transcription activation. Furthermore, Rap1A promoted epithelial‑to‑mesenchymal transition, possibly through the AKT signaling pathway. Hence, the findings of the present study indicated that Rap1A may be a potential prognostic marker or therapeutic target for ESCC.
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Project description:The efficacy of radiotherapy, one major treatment modality for esophageal squamous cell carcinoma (ESCC) is severely attenuated by radioresistance. Epithelial-to-mesenchymal transition (EMT) is a cellular process that determines therapy response and tumor progression. However, whether EMT is induced by ionizing radiation and involved in tumor radioresistance has been less studied in ESCC. Using multiple fractionated irradiation, the radioresistant esophageal squamous cancer cell line KYSE-150R had been established from its parental cell line KYSE-150. We found KYSE-150R displayed a significant EMT phenotype with an elongated spindle shape and down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker N-cadherin in comparison with KYSE-150. Furthermore, KYSE-150R also possessed some stemness-like properties characterized by density-dependent growth promotion and strong capability for sphere formation and tumorigenesis in NOD-SCID mice. Mechanical studies have revealed that WISP1, a secreted matricellular protein, is highly expressed in KYSE-150R and mediates EMT-associated radioresistance both in ESCC cells and in xenograft tumor models. Moreover, WISP1 has been demonstrated to be closely associated with the EMT phenotype observed in ESCC patients and to be an independent prognosis factor of ESCC patients treated with radiotherapy. Our study highlighted WISP1 as an attractive target to reverse EMT-associated radioresistance in ESCC and can be used as an independent prognostic factor of patients treated with radiotherapy.
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Project description:Several B-cell subsets with distinct functions and polarized cytokine profiles that extend beyond antibody production have been reported in different cancers. Here we have demonstrated that proliferating B cells were predominantly found in the peritumoral region of esophageal squamous cell carcinoma (ESCC). These B cells were enriched in tumor nests with high expression of high-mobility group box 1 (HMGB1). High densities of peritumoral proliferating B cells and concomitantly high intratumoral HMGB1 expression showed improved prognostic significance, surpassing prognostic stratification of ESCC patients based on HMGB1 positivity alone. This striking association led us to set up models to test whether cancer-derived HMGB1 could shape tumor microenvironment via modulation on B cells. Overexpression of HMGB1 in ESCC cell lines (KYSE510 and EC18) enhanced proliferation and migration of B cells. Transcriptomic analysis showed that migratory B cells exhibited high enrichment of proangiogenic genes. VEGF expression in proliferating B cells was induced upon co-culture of HMGB1-overexpressing tumor cells and B cells. Secretome array profiling of conditioned media (CM) from the co-culture revealed rich expression of proangiogenic proteins. Consequently, incubation of human umbilical vein endothelial cells with CM promoted angiogenesis in tube formation and migration assays. HMGB1 inhibitor, glycyrrhizin, abolishes all the observed proangiogenic phenotypes. Finally, co-injection of B cells and CM with HMGB1-overexpressing tumor cells, but not with glycyrrhizin, significantly enhanced tumor growth associated with increased microvascular density in ESCC xenograft mice model. Our results indicate that cancer-derived HMGB1 elevates angiogenesis in ESCC by shifting the balance toward proangiogenic signals in proliferating B cells.
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Project description:Studies have demonstrated that kallikrein-associated peptidase 11 (KLK11) is dysregulated in various cancers. However, the potential roles of KLK11 in esophageal squamous cell carcinoma (ESCC) are still unknown. In our study, we found that the expression of KLK11 in advanced ESCC was significantly down regulated than that in the adjacent tissues, and patients with higher KLK11 expression had markedly increased overall survival rates compared with those with lower KLK11 expression. In addition, up regulation of KLK11 decreased the proliferation capacity of TE-1 and EC18 cells, and down regulation of KLK11 increased the proliferation capacity. To explore the possible mechanism of KLK11 in regulating the proliferation of ESCC, the expression of the related factors in Wnt/?-catenin pathway and cell cycle-mediated factors, such as GSK-3?/p-GSK-3?, ?-catenin, Ki67, p-Rb/Rb, CDK6, CDK4 and Cyclin D1, were determined. Furthermore, KLK11 was found to be negatively correlated with the expression of ?-catenin in the nucleus, as showed by decreased expression of cyclin D1 and Ki67 through deactivation of the Wnt/?-catenin signaling pathway. XAV-939, a Wnt/?-catenin inhibitor, partially decreased the effects of KLK11 deficiency on ESCC cell proliferation. Finally, we validated that KLK11 inhibited ESCC proliferation in vivo. Our results showed that the inhibitory effects of KLK11 on the proliferation of TE-1 and EC18 cells might be associated with inhibition of Wnt/?-catenin signaling pathway. KLK11 played a key role in inhibiting ESCC carcinogenesis and progression and became a potential biomarker for poor prognosis in patients with ESCC.
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