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Neuregulin-1 (NRG1) Modulates Signaling for Autophagy and Malignancy of Esophageal Squamous Cell Carcinoma

Authors
Yen-Chiang Tseng M.D., Ph. D1#, Pei-Feng Liu PH. D2#, Yu-Ru Chen3, Wen-Hsin Yang3, Cheng-Hsin Lee2, Yih-Gang Goan M.D., Ph. D4*, Chih-Wen Shu Ph. D3*

Affiliations

  1. Division of Thoracic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
  2. Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan.
  3. Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
  4. Division of Thoracic Surgery, Department of Surgery, Pingtung Veterans General Hospital, Pingtung, Taiwan.

Introduction
The relationship between Neuregulin-1 (NRG1) and esophageal squamous cell carcinoma (ESCC) is currently not well understood. While previous studies have shown increased NRG1 levels in various cancers, its specific role in ESCC has not been clearly defined. This study seeks to explore the potential of NRG1 as a diagnostic marker or treatment option for ESCC.

Methods
This research analyzed the association between NRG1 expression and ESCC in patients from our cohort and data from The Cancer Genome Atlas (TCGA). We also examined the impact of NRG1 silencing in ESCC cells using siRNA, focusing on its effects on cell viability and autophagy. The study further investigated NRG1's signaling pathways through immunoblotting techniques.

Results
We found higher NRG1 mRNA and protein levels in tumor samples compared to normal tissues. Elevated NRG1 expression correlated with worse outcomes, especially in patients at advanced stages of ESCC. Knocking down NRG1 not only reduced its mRNA and protein levels but also affected related signaling pathways, such as p-AKT and p-RAF. This led to decreased cancer cell growth, migration, and three-dimensional sphere formation, alongside an increase in apoptotic cells. Additionally, NRG1 silencing reduced the levels of p-AKT, a negative regulator of autophagy, enhancing autophagic processes by increasing autophagosome and autolysosome formation. Combining siNRG1 with the autophagy inhibitor chloroquine (CQ) significantly increased cell death, suggesting a potent synergistic effect against ESCC cells.

Conclusion
Our findings suggest that NRG1 could be a valuable biomarker and therapeutic target in ESCC. The synergistic effect observed when combining siNRG1 with chloroquine highlights a promising strategy for ESCC treatment.