ZSH‐2208: A novel retinoid with potent anti‐tumour effects on ESCC stem cells via RARγ–TNFAIP3 axis
Abstract Backgroud Oesophageal cancer ranks among the most prevalent malignant tumours globally, primarily consisting of oesophageal squamous cell carcinoma (ESCC). Cancer stem cells (CSCs) accelerate the progression ESCC via their strong self‐renewal and tumourigenic capabilities, presenting signif...
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| Format: | Article |
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Wiley
2025-01-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70148 |
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| author | Ruoxue Chen Xuan Huang Jiayun Hou Junjie Ni Wenrui Zhao Quanlin Li Heng Jiao Xin Cao |
| author_facet | Ruoxue Chen Xuan Huang Jiayun Hou Junjie Ni Wenrui Zhao Quanlin Li Heng Jiao Xin Cao |
| author_sort | Ruoxue Chen |
| collection | DOAJ |
| description | Abstract Backgroud Oesophageal cancer ranks among the most prevalent malignant tumours globally, primarily consisting of oesophageal squamous cell carcinoma (ESCC). Cancer stem cells (CSCs) accelerate the progression ESCC via their strong self‐renewal and tumourigenic capabilities, presenting significant clinical challenges due to increased risks of recurrence and drug resistance. Methods Our previous study has reported WYC‐209, which is capable of inducing apoptosis of CSCs in melanoma and hepatoma, but is ineffective against ESCC. Additionally, clinical studies in ESCC still lack drug candidates that effectively target CSCs. Therefore, our team developed a series of novel retinoids that target retinoic acid receptors (RARs), with enhanced potency, broader efficacy and minimised toxic side effects against CSCs. Following iterative optimisation and pharmacological validation, ZSH‐2208 was identified as the most promising candidate for effectively targeting ESCC tumour‐repopulating cells (TRCs). Mechanistic exploration revealed that ZSH‐2208 inhibits the growth of ESCC‐TRCs through modulation of the RARγ–TNFAIP3 axis. The clinical significance of the key molecule TNFAIP3 in ESCC has also been demonstrated. Results This study introduces ZSH‐2208, a novel retinoid specifically targeting ESCC‐TRCs, which holds significant potential for clinical application in ESCC. Key points The ESCC‐TRCs replicates the characteristics of ESCC stem cells, which are inhibited by ZSH‐2208. In vivo and in vitro experiments demonstrated that ZSH‐2208, a novel RA analogue, effectively inhibits the growth of ESCC‐TRCs through the RARγ–TNFAIP3 axis. Low levels of TNFIP3 protein may be associated with improved survival probability in ESCC patients. |
| format | Article |
| id | doaj-art-69e8dbb6329c440a92fd704f98d329ee |
| institution | Kabale University |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj-art-69e8dbb6329c440a92fd704f98d329ee2025-01-25T04:00:38ZengWileyClinical and Translational Medicine2001-13262025-01-01151n/an/a10.1002/ctm2.70148ZSH‐2208: A novel retinoid with potent anti‐tumour effects on ESCC stem cells via RARγ–TNFAIP3 axisRuoxue Chen0Xuan Huang1Jiayun Hou2Junjie Ni3Wenrui Zhao4Quanlin Li5Heng Jiao6Xin Cao7Institute of Clinical Science, Zhongshan HospitalFudan University Shanghai Medical CollegeShanghaiChinaInstitute of Clinical Science, Zhongshan HospitalFudan University Shanghai Medical CollegeShanghaiChinaInstitute of Clinical Science, Zhongshan HospitalFudan University Shanghai Medical CollegeShanghaiChinaInstitute of Clinical Science, Zhongshan HospitalFudan University Shanghai Medical CollegeShanghaiChinaInstitute of Clinical Science, Zhongshan HospitalFudan University Shanghai Medical CollegeShanghaiChinaEndoscopy Center and Endoscopy Research Institute, Zhongshan HospitalFudan UniversityShanghaiChinaDepartment of Thoracic Surgery, Zhongshan HospitalFudan University Shanghai Medical CollegeShanghaiChinaInstitute of Clinical Science, Zhongshan HospitalFudan University Shanghai Medical CollegeShanghaiChinaAbstract Backgroud Oesophageal cancer ranks among the most prevalent malignant tumours globally, primarily consisting of oesophageal squamous cell carcinoma (ESCC). Cancer stem cells (CSCs) accelerate the progression ESCC via their strong self‐renewal and tumourigenic capabilities, presenting significant clinical challenges due to increased risks of recurrence and drug resistance. Methods Our previous study has reported WYC‐209, which is capable of inducing apoptosis of CSCs in melanoma and hepatoma, but is ineffective against ESCC. Additionally, clinical studies in ESCC still lack drug candidates that effectively target CSCs. Therefore, our team developed a series of novel retinoids that target retinoic acid receptors (RARs), with enhanced potency, broader efficacy and minimised toxic side effects against CSCs. Following iterative optimisation and pharmacological validation, ZSH‐2208 was identified as the most promising candidate for effectively targeting ESCC tumour‐repopulating cells (TRCs). Mechanistic exploration revealed that ZSH‐2208 inhibits the growth of ESCC‐TRCs through modulation of the RARγ–TNFAIP3 axis. The clinical significance of the key molecule TNFAIP3 in ESCC has also been demonstrated. Results This study introduces ZSH‐2208, a novel retinoid specifically targeting ESCC‐TRCs, which holds significant potential for clinical application in ESCC. Key points The ESCC‐TRCs replicates the characteristics of ESCC stem cells, which are inhibited by ZSH‐2208. In vivo and in vitro experiments demonstrated that ZSH‐2208, a novel RA analogue, effectively inhibits the growth of ESCC‐TRCs through the RARγ–TNFAIP3 axis. Low levels of TNFIP3 protein may be associated with improved survival probability in ESCC patients.https://doi.org/10.1002/ctm2.70148oesophageal squamous cell carcinomaretinoidretinoid acid receptor γTNFAIP3tumour‐repopulating cellsZSH‐2208 |
| spellingShingle | Ruoxue Chen Xuan Huang Jiayun Hou Junjie Ni Wenrui Zhao Quanlin Li Heng Jiao Xin Cao ZSH‐2208: A novel retinoid with potent anti‐tumour effects on ESCC stem cells via RARγ–TNFAIP3 axis Clinical and Translational Medicine oesophageal squamous cell carcinoma retinoid retinoid acid receptor γ TNFAIP3 tumour‐repopulating cells ZSH‐2208 |
| title | ZSH‐2208: A novel retinoid with potent anti‐tumour effects on ESCC stem cells via RARγ–TNFAIP3 axis |
| title_full | ZSH‐2208: A novel retinoid with potent anti‐tumour effects on ESCC stem cells via RARγ–TNFAIP3 axis |
| title_fullStr | ZSH‐2208: A novel retinoid with potent anti‐tumour effects on ESCC stem cells via RARγ–TNFAIP3 axis |
| title_full_unstemmed | ZSH‐2208: A novel retinoid with potent anti‐tumour effects on ESCC stem cells via RARγ–TNFAIP3 axis |
| title_short | ZSH‐2208: A novel retinoid with potent anti‐tumour effects on ESCC stem cells via RARγ–TNFAIP3 axis |
| title_sort | zsh 2208 a novel retinoid with potent anti tumour effects on escc stem cells via rarγ tnfaip3 axis |
| topic | oesophageal squamous cell carcinoma retinoid retinoid acid receptor γ TNFAIP3 tumour‐repopulating cells ZSH‐2208 |
| url | https://doi.org/10.1002/ctm2.70148 |
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