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缺氧通过SOX9乳酸化促进糖酵解，从而促进非小细胞肺癌细胞的干性、迁移和侵袭。

Hypoxia promotes non-small cell lung cancer cell stemness, migration, and invasion via promoting glycolysis by lactylation of SOX9.

作者信息

Yan Fei, Teng Yue, Li Xiaoyou, Zhong Yuejiao, Li Chunyi, Yan Feng, He Xia

机构信息

Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China.

Department of Medical Oncology, Nanjing Medical University, Nanjing, Jiangsu, China.

出版信息

Cancer Biol Ther. 2024 Dec 31;25(1):2304161. doi: 10.1080/15384047.2024.2304161. Epub 2024 Jan 16.

DOI:10.1080/15384047.2024.2304161
PMID:38226837
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10793688/
Abstract

BACKGROUND

Lung cancer is the deadliest form of malignancy and the most common subtype is non-small cell lung cancer (NSCLC). Hypoxia is a typical feature of solid tumor microenvironment. In the current study, we clarified the effects of hypoxia on stemness and metastasis and the molecular mechanism.

METHODS

The biological functions were assessed using the sphere formation assay, Transwell assay, and XF96 extracellular flux analyzer. The protein levels were detected by western blot. The lactylation modification was assessed by western blot and immunoprecipitation. The role of SOX9 in vivo was explored using a xenografted tumor model.

RESULTS

We observed that hypoxia promoted sphere formation, migration, invasion, glucose consumption, lactate production, glycolysis, and global lactylation. Inhibition of glycolysis suppressed cell stemness, migration, invasion, and lactylation. Moreover, hypoxia increased the levels of SOX9 and lactylation of SOX9, whereas inhibition of glycolysis reversed the increase. Additionally, knockdown of SOX9 abrogated the promotion of cell stemness, migration, and invasion. In tumor-bearing mice, overexpression of SOX9 promoted tumor growth, and inhibition of glycolysis suppressed tumor growth.

CONCLUSION

Hypoxia induced the lactylation of SOX9 to promote stemness, migration, and invasion via promoting glycolysis. The findings suggested that targeting hypoxia may be an effective way for NSCLC treatment and reveal a new mechanism of hypoxia in NSCLC.

摘要

背景

肺癌是最致命的恶性肿瘤形式，最常见的亚型是非小细胞肺癌（NSCLC）。缺氧是实体瘤微环境的典型特征。在本研究中，我们阐明了缺氧对干性和转移的影响及其分子机制。

方法

使用成球实验、Transwell实验和XF96细胞外通量分析仪评估生物学功能。通过蛋白质印迹法检测蛋白质水平。通过蛋白质印迹法和免疫沉淀法评估乳酸化修饰。使用异种移植肿瘤模型探究SOX9在体内的作用。

结果

我们观察到缺氧促进了成球、迁移、侵袭、葡萄糖消耗、乳酸生成、糖酵解和整体乳酸化。糖酵解抑制抑制了细胞干性、迁移、侵袭和乳酸化。此外，缺氧增加了SOX9的水平及其乳酸化，而糖酵解抑制则逆转了这种增加。此外，敲低SOX9消除了对细胞干性、迁移和侵袭的促进作用。在荷瘤小鼠中，SOX9的过表达促进了肿瘤生长，而糖酵解抑制则抑制了肿瘤生长。

结论

缺氧通过促进糖酵解诱导SOX9乳酸化，从而促进干性、迁移和侵袭。这些发现表明，针对缺氧可能是NSCLC治疗的有效方法，并揭示了缺氧在NSCLC中的新机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/6581c537690e/KCBT_A_2304161_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/6902e2cdc3f4/KCBT_A_2304161_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/a9305ec7a9e7/KCBT_A_2304161_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/f7c5730d6700/KCBT_A_2304161_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/56db5f8682fe/KCBT_A_2304161_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/1fa182265039/KCBT_A_2304161_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/6581c537690e/KCBT_A_2304161_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/6902e2cdc3f4/KCBT_A_2304161_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/a9305ec7a9e7/KCBT_A_2304161_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/f7c5730d6700/KCBT_A_2304161_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/56db5f8682fe/KCBT_A_2304161_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/1fa182265039/KCBT_A_2304161_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b5c/10793688/6581c537690e/KCBT_A_2304161_F0006_OC.jpg

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