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神经酰胺激酶通过上调Ras/ERK和PI3K/Akt信号通路介导三阴性乳腺癌的内在耐药性及对化疗的低反应性。

Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple-negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways.

作者信息

Zhu Shan, Xu Yulin, Wang Lijun, Liao Shichong, Wang Yuan, Shi Manman, Tu Yi, Zhou Yurong, Wei Wen

机构信息

Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.

Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.

出版信息

Cancer Cell Int. 2021 Jan 11;21(1):42. doi: 10.1186/s12935-020-01735-5.

DOI:10.1186/s12935-020-01735-5
PMID:33430896
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7802356/
Abstract

BACKGROUND

Clinical management of triple-negative breast cancer (TNBC) patients remain challenging because of the development of chemo-resistance. Identification of biomarkers for risk stratification of chemo-resistance and therapeutic decision-making to overcome such resistance is thus necessary.

METHODS

Retrospective analysis was performed to identify potential stratification biomarkers. The levels of ceramide kinase (CERK) was determined in breast cancer patients. The roles of CERK and its downstream signaling pathways were analysed using cellular and biochemical assays.

RESULTS

CERK upregulation was identified as a biomarker for chemotherapeutic response in TNBC. A > 2-fold change in CERK (from tumor)/CERK (from normal counterpart) was significantly associated with chemo-resistance (OR = 2.66, 95% CI 1.18-7.34), P = 0.04. CERK overexpression was sufficient to promote TNBC growth and migration, and confer chemo-resistance in TNBC cell lines, although this resistance could be overcome via CERK inhibition. Mechanistic studies suggest that CERK mediates intrinsic resistance and inferior response to chemotherapy in TNBC by regulating multiple oncogenic pathways such as Ras/ERK, PI3K/Akt/mTOR, and RhoA.

CONCLUSIONS

Our work provides an explanation for the heterogeneity of chemo-response across TNBC patients and demonstrates that CERK inhibition offers a therapeutic strategy to overcome treatment resistance.

摘要

背景

由于化疗耐药性的出现，三阴性乳腺癌（TNBC）患者的临床管理仍然具有挑战性。因此，有必要识别用于化疗耐药风险分层和克服这种耐药性的治疗决策的生物标志物。

方法

进行回顾性分析以识别潜在的分层生物标志物。测定了乳腺癌患者中神经酰胺激酶（CERK）的水平。使用细胞和生化分析方法分析了CERK及其下游信号通路的作用。

结果

CERK上调被确定为TNBC化疗反应的生物标志物。CERK（肿瘤组织）/CERK（正常组织）的变化>2倍与化疗耐药性显著相关（OR = 2.66，95% CI 1.18 - 7.34），P = 0.04。CERK过表达足以促进TNBC的生长和迁移，并赋予TNBC细胞系化疗耐药性，尽管这种耐药性可通过抑制CERK来克服。机制研究表明，CERK通过调节多种致癌途径，如Ras/ERK、PI3K/Akt/mTOR和RhoA，介导TNBC的内在耐药性和对化疗的不良反应。

结论

我们的工作解释了TNBC患者化疗反应的异质性，并证明抑制CERK提供了一种克服治疗耐药性的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/d37e0d2eff7b/12935_2020_1735_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/f969f8c1fec9/12935_2020_1735_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/5add695ee9e6/12935_2020_1735_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/bca407aab3bc/12935_2020_1735_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/c485316d05f6/12935_2020_1735_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/bc975c1f129d/12935_2020_1735_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/d37e0d2eff7b/12935_2020_1735_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/f969f8c1fec9/12935_2020_1735_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/5add695ee9e6/12935_2020_1735_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/bca407aab3bc/12935_2020_1735_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/c485316d05f6/12935_2020_1735_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/bc975c1f129d/12935_2020_1735_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fe/7802356/d37e0d2eff7b/12935_2020_1735_Fig6_HTML.jpg

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