Epiregulin increases stemness-associated genes expression and promotes chemoresistance of non-small cell lung cancer via ERK signaling

  • Stem Cell Res Ther. 2022 May 12;13(1):197. doi: 10.1186/s13287-022-02859-3.
Yujia Zhang   #  1 ,  Fengjun Qiu   #  1 ,  Tingjie Ye   #  1 ,  Sau Har Lee  2 ,  Jiatuo Xu  1 ,  Lingyan Jia  3 ,  Rui Zeng  1 ,  Xiaoling Wang  1 ,  Xudong Hu  1 ,  Xiaofeng Yan  1 ,  Hua Li  1 ,  Yanlin Lu  4 ,  Xiaoling Wang  3 ,  Rilei Jiang  5 ,  Wei Xu  6
Affiliations
  • 1. School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 2. School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Lakeside Campus, Subang Jaya, Selangor, Malaysia.
  • 3. ZJU-UoE Institute, Zhejiang University School of Medicine, Zhejiang University, Haining, China.
  • 4. Department of Oncology and Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 5. School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. [email protected].
  • 6. School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. [email protected].
  • # Contributed equally.
PMID: 35551652 DOI: 10.1186/s13287-022-02859-3
Abstract

Background: Chemoresistance often causes the failure of treatment and death of patients with advanced non-small-cell lung Cancer. However, there is still no resistance genes signature and available enriched signaling derived from a comprehensive RNA-Seq data analysis of lung Cancer patients that could act as a therapeutic target to re-sensitize the acquired resistant Cancer cells to chemo-drugs. Hence, in this study, we aimed to identify the resistance signature for clinical lung Cancer patients and explore the regulatory mechanism.

Method: Analysis of RNA-Seq data from clinical lung Cancer patients was conducted in R studio to identify the resistance signature. The resistance signature was validated by survival time of lung Cancer patients and qPCR in chemo-resistant cells. Cytokine application, small-interfering RNA and pharmacological inhibition approaches were applied to characterize the function and molecular mechanism of EREG and downstream signaling in chemoresistance regulation via stemness.

Results: The RTK and vitamin D signaling were enriched among resistance genes, where 6 genes were validated as resistance signature and associated with poor survival in patients. EREG/ERK signaling was activated by chemo-drugs in NSCLC cells. EREG protein promoted the NSCLC resistance to chemo-drugs by increasing stemness genes expression. Additionally, inhibition of EREG/ErbB had downregulated ERK signaling, resulting in decreased expression of stemness-associated genes and subsequently re-sensitized the resistant NSCLC cells and spheres to chemo-drugs.

Conclusions: These findings revealed 6 resistance genes signature and proved that EREG/ErbB regulated the stemness to maintain chemoresistance of NSCLC via ERK signaling. Therefore, targeting EREG/ErbB might significantly and effectively resolve the chemoresistance issue.

Keywords
Chemoresistance; EREG; ERK signaling; Non-small cell lung cancer; Receptor tyrosine kinase; Stemness.
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