Open Access

ARTICLE

Knockdown of HE4 suppresses tumor growth and invasiveness in lung adenocarcinoma through regulation of EGFR signaling

YUE ZHANG^1,#, WENYU YANG^1,#, XIAOWANG HAN^1,#, YUE QIAO¹, HAITAO WANG², TING CHEN¹, TIANYING LI¹, WEN-BIN OU^1,*
1 Department of Biopharmaceutics, College of Life Sciences and Medicine, Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China
2 Department of Thoracic Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, 310014, China
* Corresponding Author: WEN-BIN OU. Email:
(This article belongs to the Special Issue: Signaling Pathway Crosstalk in Malignant Tumors: Molecular Targets and Combinatorial Therapeutics)

Oncology Research https://doi.org/10.32604/or.2024.045025

Received 15 August 2023; Accepted 02 January 2024; Published online 06 February 2024

Abstract

It has been shown that the high expression of human epididymis protein 4 (HE4) in most lung cancers is related to the poor prognosis of patients, but the mechanism of pathological transformation of HE4 in lung cancer is still unclear. The current study is expected to clarify the function and mechanism of HE4 in the occurrence and metastasis of lung adenocarcinoma (LUAD). Immunoblotting evaluated HE4 expression in lung cancer cell lines and biopsies, and through analysis of The Cancer Genome Atlas (TCGA) dataset. Frequent HE4 overexpression was demonstrated in LUAD, but not in lung squamous cell carcinoma (LUSC), indicating that HE4 can serve as a biomarker to distinguish between LUAD and LUSC. HE4 knockdown significantly inhibited cell growth, colony formation, wound healing, and invasion, and blocked the G₁-phase of the cell cycle in LUAD cell lines through inactivation of the EGFR signaling downstream including PI3K/AKT/mTOR and RAF/MAPK pathways. The first-line EGFR inhibitor gefitinib and HE4 shRNA had no synergistic inhibitory effect on the growth of lung adenocarcinoma cells, while the third-line EGFR inhibitor osimertinib showed additive anti-proliferative effects. Moreover, we provided evidence that HE4 regulated EGFR expression by transcription regulation and protein interaction in LUAD. Our findings suggest that HE4 positively modulates the EGFR signaling pathway to promote growth and invasiveness in LUAD and highlight that targeting HE4 could be a novel strategy for LUAD treatment.

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Keywords

Lung adenocarcinoma; Human epididymis protein 4; Epidermal growth factor receptor; Biomarker; Targeted therapies

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