Journal Article

Ubiquitous mitochondrial creatine kinase promotes the progression of gastric cancer through a JNK-MAPK/JUN/HK2 axis regulated glycolysis

Wang, Dehai, Zhou, Yan, Ding, Yinlu, Mi, Yushuai, Liu, Bingtian, Wen, Yugang, Wang, Tianshi, Wang, Yuan, Zang, Yifeng, Liu, Ziping, Li, Quanhui

2023

Overview

Background Ubiquitous mitochondrial creatine kinase (uMtCK) transfers high-energy phosphates from mitochondrially generated ATP to creatine to generate phosphocreatine. uMtCK overexpression has been reported in several malignant tumors, however, the clinical significance and impact of uMtCK in gastric cancer (GC) has not been comprehensively studied. Methods We first examined uMtCK expression in GC by quantitative real-time PCR and western blot assays. Then the clinicopathological significance of aberrant uMtCK expression was determined by immunohistochemical staining in a GC tissue microarray. Kaplan–Meier analysis was used for survival analysis. The biological functions of uMtCK in GC cells were explored by wound-healing, transwell assays and glucose metabolism assays in vitro as well as a liver metastasis model by spleen injection in nude mice in vivo. Results We verified that the expression of uMtCK was substantially elevated in GC tissues, significantly associating with a poorer prognosis in GC patients, especially for those with advanced stage. In univariate and multivariate analyses, uMtCK expression emerged as an independent prognostic factor for both disease-free survival and overall survival. Functionally, we demonstrated that uMtCK promoted glycolysis in GC cells and facilitated their migration, invasion and liver metastasis in vitro and in vivo. Mechanistically, uMtCK enhanced GC progression in a HK2-dependent glycolysis via acting the JNK-MAPK/JUN signaling pathway. Conclusions uMtCK could serve as a novel independent prognostic biomarker as well as potential therapeutic target for GC patients, particularly for GC patients with an advanced UICC stage and tumor recurrence.

• Publisher: Springer Nature Singapore,Springer Nature B.V
• Subject: Abdominal Surgery / Animals / Biomarkers / Breast cancer / Cancer Research / Cell Line, Tumor / Cell Proliferation / Creatine / Creatine kinase / Creatine Kinase, Mitochondrial Form - metabolism / Disease / Gastric cancer / Gastroenterology / Gene Expression Regulation, Neoplastic / Glucose metabolism / Glycolysis / Humans / Kinases / Liver / Liver Neoplasms / Lymphatic system / MAP kinase / Medical prognosis / Medicine / Medicine & Public Health / Metastases / Metastasis / Mice / Mice, Nude / Mitochondria / Oncology / Original / Original Article / Phosphocreatine / Prognosis / Protein expression / Proteins / Signal transduction / Stomach Neoplasms - pathology / Surgical Oncology / Therapeutic targets / Tumors / Wound healing