ABSTRACT
Patients with stage II or III colorectal cancer (CRC) exhibit various clinical outcomes after radical treatments. The 5-year survival rate was between 50 and 87%. However, the underlying mechanisms of the variation remain unclear. Here we show that AMPKα1 is overexpressed in CRC patient specimens and the high expression is correlated with poor patient survival. We further reveal a previously unrecognized function of AMPKα1, which maintains high level of reduced glutathione to keep reduction-oxidation reaction (redox) homeostasis under stress conditions, thus promoting CRC cell survival under metabolic stress in vitro and enhancing tumorigenesis in vivo. Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity. Suppression of AMPKα1 by using nano-sized polymeric vector induces a favorable therapeutic effect, especially when in combination with oxaliplatin. Our study uncovers a novel function of AMPKα1 in redox regulation and identifies a promising therapeutic strategy for treatment of CRC.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinogenesis/pathology , Colorectal Neoplasms/pathology , Glutathione Reductase/metabolism , AMP-Activated Protein Kinases/genetics , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Line, Tumor , Cell Survival , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/mortality , Drug Synergism , Female , Gene Knockdown Techniques , Humans , Kaplan-Meier Estimate , Male , Mice , Middle Aged , Neoplasm Staging , Oxaliplatin/pharmacology , Oxaliplatin/therapeutic use , Oxidation-Reduction , Phosphorylation , RNA, Small Interfering/metabolism , Reactive Oxygen Species/metabolism , Stress, Physiological , Survival Rate , Threonine/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Esophageal squamous dysplasia is believed to be the precursor lesion of esophageal squamous cell carcinoma (ESCC); however, the genetic evolution from dysplasia to ESCC remains poorly understood. Here, we applied multi-region whole-exome sequencing to samples from two cohorts, 45 ESCC patients with matched dysplasia and carcinoma samples, and 13 tumor-free patients with only dysplasia samples. Our analysis reveals that dysplasia is heavily mutated and harbors most of the driver events reported in ESCC. Moreover, dysplasia is polyclonal, and remarkable heterogeneity is often observed between tumors and their neighboring dysplasia samples. Notably, copy number alterations are prevalent in dysplasia and persist during the ESCC progression, which is distinct from the development of esophageal adenocarcinoma. The sharp contrast in the prevalence of the 'two-hit' event on TP53 between the two cohorts suggests that the complete inactivation of TP53 is essential in promoting the development of ESCC.The pathogenesis of oesophageal squamous cell carcinoma is a multi-step process but the genetic determinants behind this progression are unknown. Here the authors use multi-region exome sequencing to comprehensively investigate the genetic evolution of precursor dysplastic lesions and untransformed oesophagus.
Subject(s)
Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Exome , Mutation , Precancerous Conditions/genetics , DNA Copy Number Variations , Esophageal Squamous Cell Carcinoma , Humans , Loss of Heterozygosity , Precancerous Conditions/pathology , Sequence Analysis, DNA/methods , Tumor Suppressor Protein p53/geneticsABSTRACT
OBJECTIVE: To investigate human papillomavirus (HPV) infection and genotyping in patients with cervical cancer in Guangzhou in the last 3 decades. METHODS: HPV L1 gene fragment in paraffin-embedded cervical cancer samples was amplified by HPV-specific PCR with consensus primers, and typing of HPV strains was performed on the basis of sequence analysis of the PCR products. RESULTS: The positivity rates of HPV DNA was 26.2% in the 99 cases of cervical cancer. Five HPV genotypes were identified including HPV16, 18, 33, 52 and 58. CONCLUSION: HPV16, 58 and 33 are the most common genotypes of HPV, accounting for over 88.4% in the total infected cases, suggesting that the HPV genotypes closely related to cervical cancer is more centralized in Guangzhou.
