CTSG restraines the proliferation and metastasis of head and neck squamous cell carcinoma by blocking the JAK2/STAT3 pathway

Hongting Hua; Xiaonan Yang; Dongdong Meng; Ruijia Gan; Nuo Chen; Lanqiaofeng He; Dong Wang; Wanjin Jiang; Dongyu Si; Xu Wang; Xiaomin Zhang; Xiang Wei; Yiming Wang; Bao Li; Huabing Zhang; Chaobing Gao

doi:10.1016/j.cellsig.2024.111562

CTSG restraines the proliferation and metastasis of head and neck squamous cell carcinoma by blocking the JAK2/STAT3 pathway

Cell Signal. 2024 Dec 11:127:111562. doi: 10.1016/j.cellsig.2024.111562. Online ahead of print.

Authors

Hongting Hua¹, Xiaonan Yang¹, Dongdong Meng¹, Ruijia Gan¹, Nuo Chen¹, Lanqiaofeng He¹, Dong Wang¹, Wanjin Jiang², Dongyu Si¹, Xu Wang³, Xiaomin Zhang⁴, Xiang Wei⁴, Yiming Wang⁴, Bao Li⁵, Huabing Zhang⁶, Chaobing Gao⁷

Affiliations

¹ Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China.
² Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, China.
³ Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China.
⁴ Department of Biochemistry & Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, Anhui, China.
⁵ Synthetic Laboratory of School of Basic Medicine Sciences, Anhui Medical University, Hefei 230032, China.
⁶ Department of Biochemistry & Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, Anhui, China. Electronic address: huabingzhang@ahmu.edu.cn.
⁷ Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China. Electronic address: gaochaobing@ahmu.edu.cn.

PMID: 39672353
DOI: 10.1016/j.cellsig.2024.111562

Abstract

Background: Head and neck squamous cell carcinoma (HNSC) is recognized as the sixth most prevalent cancer globally, with around 900,000 new cases diagnosed each year. The management of HNSC poses significant challenges due to its rising incidence and suboptimal treatment outcomes in many patients. Thus, understanding the underlying molecular mechanisms that drive the onset and advancement of HNSC is crucial in order to steer the creation of novel treatment strategies. Previous researches have suggested that Cathepsin G (CTSG), a serine protease, may play a role in tumorigenesis, but its exact function in HNSC is still unknown.

Methods: The TCGA and GTEx datasets were utilized to examine the expression and potential role of CTSG in pancancer. CTSG expression in HNSC tissues and normal tissues was analyzed using qRT-PCR, Western blot and immunohistochemistry techniques. The effects of altering CTSG expression on proliferation, migration, and apoptosis of HNSC cells were evaluated using various tests such as MTT assays, colony formation assays, wound-healing assays, transwell assays, flow cytometry, and xenograft tumor growth models. The functionality of CTSG on the JAK2/STAT3 pathway was validated using activators and inhibitors of this pathway after comfirming that CTSG could regulate this pathway.

Results: In our study, we indicated that CTSG expression in HNSC tumor tissues was significantly lower than in adjacent normal tissues and CTSG gene level was positively correlated with patient prognosis. Additionally, we observed a decrease in tumor proliferation and migration, as well as an increase in apoptosis, following CTSG overexpression. Conversely, opposite effects were noted upon CTSG knockdown. Mechanistically, CTSG overexpression inhibited JAK2/STAT3 signaling, while CTSG knockdown activated it. This was confirmed by using IL-6 and JAK2 inhibitor.

Conclusion: CTSG impedes the proliferation and metastasis of HNSC in vivo and in vitro. CTSG is potential to act as a cancer suppressor in HNSC by focusing on the JAK2/STAT3 signaling pathway, indicating its possible use as a diagnostic marker and treatment target for HNSC.

Keywords: CTSG; Head and neck squamous cell carcinoma; JAK2; STAT3.