Depleting CBR1 increases chemosensitivity by reducing stemness and quiescence traits in non-small cell lung cancer

Weiwen LI; Jialu ZHAO; Weihong LAN; Xiaofei YE; Kejing YING

doi:10.1631/jzus.B2400509

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Research Article | Updated：2025-12-31

Depleting CBR1 increases chemosensitivity by reducing stemness and quiescence traits in non-small cell lung cancer
Depleting CBR1 increases chemosensitivity by reducing stemness and quiescence traits in non-small cell lung cancer
CBR1通过调节细胞干性和静止状态介导非小细胞肺癌化疗敏感性
Journal of Zhejiang University-SCIENCE B Vol. 26, Issue 12, Pages: 1216-1232(2025)
Affiliations：

1.Department of Respiratory and Critical Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
2.Department of Respiratory and Critical Medicine, The Fifth Affiliated Hospital to Wenzhou Medical University, Lishui 323000, China
Funds：
DOI：10.1631/jzus.B2400509
CLC：
CSTR：
Received：14 October 2024，

Revised：2025-01-06，

Published Online：17 December 2025，

Published：31 December 2025
Accepted：

李伟文,赵嘉璐,蓝伟红等.CBR1通过调节细胞干性和静止状态介导非小细胞肺癌化疗敏感性[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(12):1216-1232.

Weiwen LI, Jialu ZHAO, Weihong LAN, et al. Depleting CBR1 increases chemosensitivity by reducing stemness and quiescence traits in non-small cell lung cancer[J]. Journal of Zhejiang University-SCIENCE B, 2025, 26(12): 1216-1232.
李伟文,赵嘉璐,蓝伟红等.CBR1通过调节细胞干性和静止状态介导非小细胞肺癌化疗敏感性[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(12):1216-1232. DOI： 10.1631/jzus.B2400509.

Weiwen LI, Jialu ZHAO, Weihong LAN, et al. Depleting CBR1 increases chemosensitivity by reducing stemness and quiescence traits in non-small cell lung cancer[J]. Journal of Zhejiang University-SCIENCE B, 2025, 26(12): 1216-1232. DOI： 10.1631/jzus.B2400509.

摘要

羰基还原酶1（CBR1）作为短链脱氢酶/还原酶（SDR）超家族一员，与肿瘤进展和治疗抵抗有关，但其在非小细胞肺癌（NSCLC）中的具体作用尚不明确。本研究检测了CBR1在NSCLC组织和细胞系中的表达，采用基因干扰和药物抑制方法，评估了CBR1对肿瘤干性、化疗敏感性和细胞静止状态的影响，进一步探讨了其潜在机制。研究结果表明，CBR1在NSCLC组织和细胞系中表达升高，且顺铂（CDDP）处理可进一步诱导其表达上调。通过基因干扰下调CBR1表达后，CD133阳性细胞百分比显著降低，OCT4和SOX2的表达下降，同时细胞对CDDP的化疗敏感性增强。CBR1特异性抑制剂hydroxy-PP-Me（PP-Me）显著增加了CDDP的细胞毒性，并抑制了细胞干性。此外，sh-CBR1或PP-Me处理能够有效改变NSCLC细胞的静止状态，具体表现为G0期细胞比例和p27表达下降而cyclin D1和pRb表达上升。进一步研究发现，SETD4作为介导NSCLC细胞干性、化疗敏感性和静止状态的因子，在sh-CBR1或PP-Me处理后表达下调而过表达SETD4则可逆转由CBR1抑制所增强的化疗敏感性。在A549异种移植模型中，PP-Me与CDDP联合治疗的抑瘤效果显著优于单药治疗。综上所述，抑制CBR1可通过阻断肿瘤干性与静止期，增强NSCLC对CDDP的化疗敏感性。

Abstract

Carbonyl reductase 1 (CBR1)

a member of the short-chain dehydrogenase/reductase (SDR) superfamily

is implicated in tumor progression and treatment resistance. However

its role in non-small cell lung cancer (NSCLC) remains unclear. This study examined CBR1 expression in NSCLC tissues and cell lines

using gene interference and pharmacological inhibition to assess its impact on stemness

chemosensitivity

and quiescence

and to explore underlying mechanisms. Our findings indicate that CBR1 expression is elevated in NSCLC tissues and cell lines

and further increases in the presence of cisplatin (CDDP). Gene interference reducing CBR1 expression significantly decreased the percentage of cluster of differentiation 133 (CD133)-positive cells and the expression of octamer-binding transcription factor 4 (OCT4) and SRY (sex determining region Y)-box 2 (SOX2)

while enhancing CDDP chemosensitivity. The CBR1-specific inhibitor hydroxy-PP-Me (PP-Me) markedly increased CDDP cytotoxicity and reduced stemness. Additionally

CBR1 inhibition via short hairpin RNA (shRNA) CBR1 (sh-CBR1) or PP-Me disrupted NSCLC cell quiescence

as shown by a decrease in G0 phase cells and p27 expression

alongside an increase in cyclin D1 and phospho-retinoblastoma (pRb) expression. Furthermore

SET domain-containing protein 4 (SETD4)

which mediates stemness

chemosensitivity

and quiescence in NSCLC cells

was downregulated by sh-CBR1 or PP-Me treatment. The overexpression of SETD4 counteracted the enhanced chemosensitivity resulting from CBR1 inhibition. In A549 xenografts

combined PP-Me and CDDP therapy significantly inhibited tumor growth compared to either treatment alone. In conclusion

CBR1 inhibition enhances CDDP chemosensitivity by suppressing stemness and quiescence in NSCLC.

关键词

Keywords

references

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