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Purpose <p>A chromatin remodeling-related gene, cat eye syndrome chromosome region, candidate 2 (<i>CECR2</i>) was identified as candidate gene associated with aggressive phenotypes of esophageal squamous cell carcinoma (ESCC) in a transcriptome analysis. Here, we aimed to elucidate its role and potential for clinical application.</p> Methods <p>We evaluated ESCC cell lines modulating <i>CECR2</i> expression in vitro. Signaling analysis and inhibitor experiments were conducted to reveal its potential mechanism. Mouse subcutaneous models were established to confirm the effect of knockdown and inhibitor. Expressions of <i>CECR2</i> on mRNA level were analyzed by qPCR and protein level by TMA, respectively, in two cohorts.</p> Results <p><i>CECR2</i> was significantly upregulated in cancer tissue compared to normal tissue. <i>CECR2</i> knockdown suppressed metastasis-related biological functions of ESCC cells and increased the sensitivity to principal anticancer reagents for treatment of ESCC, 5-FU and cisplatin. In addition, forced overexpression of <i>CECR2</i> enhanced proliferation of low-<i>CECR2</i>-expressed cell line. Mechanistically, CECR2 upregulates NF-κB signaling, downregulates acetylated p53 expressions, and activates AKT signaling to enhance NF-κB signaling. Pharmacological inhibition of CECR2 by NVS-CECR2-1 induced cell apoptosis. In mouse subcutaneous models, permanent knockdown mediated by sh<i>CECR2</i> significantly inhibited tumor growth compared to shControl group; tumor growth was inhibited by a continual cycle of intraperitoneal administration of NVS-CECR2-1 compared to PBS only group. Analysis of two cohorts both demonstrated a significant association between high <i>CECR2</i> mRNA/protein expression levels and poor prognosis.</p> Conclusion <p>Upregulation of <i>CECR2</i> in ESCC promotes tumor aggressiveness and may serve as a potential therapeutic target for the treatment of ESCC.</p>

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Overexpression of cat eye syndrome chromosome region, candidate 2 in esophageal squamous carcinoma cell promotes tumor aggressiveness by facilitating NF-κB signaling and inhibition of p53-associated apoptosis

  • 期刊论文

  • 发表日期：

    2025年8月4日

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  • Haote Zhu,
  • Mitsuro Kanda,
  • Dai Shimizu,
  • Yusuke Sato,
  • Tuvshin Bayasgalan,
  • Mohammad Hussain Hamrah,
  • Flor Esther Garza Martinez,
  • Takahiro Shinozuka,
  • Kotaro Aoki,
  • Shinichi Umeda,
  • Hideki Takami,
  • Norifumi Hattori,
  • Masamichi Hayashi,
  • Chie Tanaka,
  • Goro Nakayama,
  • Yasuhiro Kodera

摘要

Purpose

A chromatin remodeling-related gene, cat eye syndrome chromosome region, candidate 2 (CECR2) was identified as candidate gene associated with aggressive phenotypes of esophageal squamous cell carcinoma (ESCC) in a transcriptome analysis. Here, we aimed to elucidate its role and potential for clinical application.

Methods

We evaluated ESCC cell lines modulating CECR2 expression in vitro. Signaling analysis and inhibitor experiments were conducted to reveal its potential mechanism. Mouse subcutaneous models were established to confirm the effect of knockdown and inhibitor. Expressions of CECR2 on mRNA level were analyzed by qPCR and protein level by TMA, respectively, in two cohorts.

Results

CECR2 was significantly upregulated in cancer tissue compared to normal tissue. CECR2 knockdown suppressed metastasis-related biological functions of ESCC cells and increased the sensitivity to principal anticancer reagents for treatment of ESCC, 5-FU and cisplatin. In addition, forced overexpression of CECR2 enhanced proliferation of low-CECR2-expressed cell line. Mechanistically, CECR2 upregulates NF-κB signaling, downregulates acetylated p53 expressions, and activates AKT signaling to enhance NF-κB signaling. Pharmacological inhibition of CECR2 by NVS-CECR2-1 induced cell apoptosis. In mouse subcutaneous models, permanent knockdown mediated by shCECR2 significantly inhibited tumor growth compared to shControl group; tumor growth was inhibited by a continual cycle of intraperitoneal administration of NVS-CECR2-1 compared to PBS only group. Analysis of two cohorts both demonstrated a significant association between high CECR2 mRNA/protein expression levels and poor prognosis.

Conclusion

Upregulation of CECR2 in ESCC promotes tumor aggressiveness and may serve as a potential therapeutic target for the treatment of ESCC.