ATP-Dependent Lon Protease Contributes to Helicobacter pylori-Induced Gastric Carcinogenesis.
Helicobacter pylori infection is the strongest risk factor for development of gastric cancer. Host cellular stress responses, including inflammatory and immune responses, have been reported highly linked to H. pylori-induced carcinogenesis. However, whether mitochondrial regulation and metabolic reprogramming, which are potently associated with various cancers, play a role in H. pylori-induced gastric carcinogenesis is largely unknown. Here we revealed that Lon protease (Lonp1), which is a key inductive of mitochondrial unfolded protein response (UPR(mt)) and is required to maintain the mitochondrial quality, was greatly induced in H. pylori infected gastric epithelial cells. Importantly, we uncovered that knockdown of Lonp1 expression significantly diminished the metabolic switch to glycolysis and gastric cell proliferation associated with low multiplicity of H. pylori infection. In addition, Lonp1 overexpression in gastric epithelial cells also promoted glycolytic switch and cell overgrowth, suggesting H. pylori effect is Lonp1 dependent. We further demonstrated that H. pylori induced Lonp1 expression and cell overgrowth, at least partially, via HIF-1α regulation. Collectively, our results concluded the relevance of Lonp1 for cell proliferation and identified Lonp1 as a key regulator of metabolic reprogramming in H. pylori-induced gastric carcinogenesis.
Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, People's Republic of China.
Bin
B
Luo
Department of Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100043, People's Republic of China.
Minggang
M
Wang
Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, People's Republic of China.
Nengyi
N
Hou
Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, People's Republic of China.
Xiao
X
Hu
Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, People's Republic of China.
Guiqing
G
Jia
Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, People's Republic of China.
Xianpeng
X
Qin
Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, People's Republic of China.
Xiaofei
X
Zuo
Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, People's Republic of China.
Yang
Y
Liu
Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, People's Republic of China.
Kun
K
Luo
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Wei
W
Song
Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, People's Republic of China. Electronic address: pangmh2000@163.com.
Kang
K
Wang
Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, People's Republic of China. Electronic address: pangshattuck@126.com.
Minghui
M
Pang
D049069:ATP-Dependent Proteases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D016000:Cluster Analysis; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006019:Glycolysis; D016481:Helicobacter Infections / Q000150:complications* / Q000382:microbiology*; D016480:Helicobacter pylori; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D013274:Stomach Neoplasms / Q000209:etiology* / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D024101:Mitochondrial Proteins; D049069:ATP-Dependent Proteases; C000595973:LONP1 protein, human