Xianke Lin - Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Jiajia Pan - Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China
Hammza Hamoudi - Zhejiang University College of Medicine, Hangzhou, China
Jiren Yu - Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Objective(s): ۵-Fluorouracil (۵-FU) is currently the main drug used in chemotherapy for gastric cancer (GC). The main clinical problems of ۵-FU therapy are insensitivity and acquired resistance to ۵-FU. The mechanism of GC cell resistance to ۵-FU is currently unknown.Materials and Methods: This study employed next-generation sequencing (NGS) to analyze the differentially expressed genes (DEGs) in chemotherapy-sensitive and non-sensitive GC tissues. In addition, a bioinformatics analysis was conducted using the GC dataset of GEO, and further validated and explored through in vitro experiments.Results: Thyroid adenoma-associated gene (THADA) was highly expressed in GC tissues from chemotherapy-sensitive patients and was an independent prognostic factor in GC patients receiving postoperative ۵-FU adjuvant chemotherapy. Notably, heightened THADA expression in GC cells was associated with the down-regulation of autophagy-related proteins (LC-۳, ATG۱۳, ULK۱, and TFEB). Furthermore, the PI۳K/AKT/mTOR signaling pathway and mTORC۱ signaling pathway were remarkably increased in patients with elevated THADA expression. THADA expression was associated with mTOR, the core protein of the mTOR signaling pathway, and related proteins involved in regulating the mTORC۱ signaling pathway (mLST۸, RHEB, and TSC۲). THADA exhibited inhibitory effects on autophagy and augmented the sensitivity of GC cells to ۵-FU through the PI۳K/AKT/mTOR signaling pathway.Conclusion: The findings suggest that THADA may be involved in the regulatory mechanism of GC cell sensitivity to ۵-FU. Consequently, the detection of THADA in tumor tissues may bring clinical benefits, specifically for ۵-FU-related chemotherapy administered to GC patients with elevated THADA expression.

Autophagy, Fluorouracil, Human, Stomach Neoplasms THADA protein, TOR Serine-Threonine- Kinases