ERO1L promotes IL6/sIL6R signaling and regulates MUC16 expression to promote CA125 secretion and the metastasis of lung cancer cells

Yuanyuan Lei,Jianbing Huang,Guochao Zhang,Shuangshuang Mao,Nan Sun,Chengming Liu,Zhanyu Wang,Lingling Fang,Zhiliang Lu,Xinfeng Wang,Sufei Zheng,Jie He,Yun Che,Ruochuan Zang

doi:10.1038/s41419-020-03067-8

Abstract

The abnormal secretion of CA125, a classic tumor marker, is usually related to a poor prognosis in various tumors. Thus, this study aimed to explore the potential mechanisms that promote CA125 secretion in lung cancer. By querying the database, the gene endoplasmic reticulum oxidoreductase 1L (ERO1L) was identified and chosen as the research subject. The antibody chips were used to screen the lung cancer cell supernatant and found that the most obvious secreted protein was CA125. ERO1L was found to promote the secretion of IL6R by affecting the formation of disulfide bonds. IL6R bound to IL6 and triggered the activation of the NF-κB signaling pathway. Then, NF-κB bound to the promoter of MUC16, resulting in overexpression of MUC16. The extracellular segment of MUC16 was cleaved to form CA125, while the C terminus of MUC16 promoted the EMT phenotype and the release of IL6, forming a positive feedback pathway. In conclusion, ERO1L might affect the secretion of CA125 through the IL6 signaling pathway and form a positive feedback loop to further promote the development of lung cancer. This might expand the application scope of CA125 in lung cancer.

Highlights

Lung cancer ranks first in morbidity and mortality[1,2].The main cause of lung cancer-related death is the expansion of primary tumors and spreading distant metastases
We found that the secondranked gene endoplasmic reticulum oxidoreductase 1L (ERO1L) was an enzyme that affects the formation of disulfide bonds
The results showed that the expression of ERO1L in cancerous tissues was much higher than that in adjacent tissues (Fig. 1D)

Summary

Introduction

Lung cancer ranks first in morbidity and mortality[1,2]. The main cause of lung cancer-related death is the expansion of primary tumors and spreading distant metastases. The most classic prognostic markers of lung cancer are protein markers, mainly secreted proteins. An abnormal increase in protein tumor markers is related to the poor prognosis of many tumors. Many markers only play a role in indicating progression of certain disease. It is unclear why their abnormal secretion is related to the malignant progression of tumors. This secretion may be a result rather than a cause of disease progression. If the potential source that affects the secretion of these proteins can be

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Conclusion