AMPKα Modulation in Cancer Progression: Multilayer Integrative Analysis of the Whole Transcriptome in Asian Gastric Cancer

Abstract

Gastric cancer is the most common cancer in Asia and most developing countries. Despite the use of multimodality therapeutics, it remains the second leading cause of cancer death in the world. To identify the molecular underpinnings of gastric cancer in the Asian population, we applied an RNA-sequencing approach to gastric tumor and noncancerous specimens, generating 680 million informative short reads to quantitatively characterize the entire transcriptome of gastric cancer (including mRNAs and microRNAs). A multi-layer analysis was then developed to identify multiple types of transcriptional aberrations associated with different stages of gastric cancer, including differentially expressed mRNAs, recurrent somatic mutations and key differentially expressed microRNAs. Through this approach, we identified the central metabolic regulator AMPK-α as a potential functional target in Asian gastric cancer. Further, we experimentally demonstrated the translational relevance of this gene as a potential therapeutic target for early-stage gastric cancer in Asian patients. Together, our findings not only provide a valuable information resource for identifying and elucidating the molecular mechanisms of Asian gastric cancer, but also represent a general integrative framework to develop more effective therapeutic targets.

AMP-Activated Protein Kinase 2 Isoform Suppression in Primary Breast Cancer Alters AMPK Growth Control and Apoptotic Signaling

“…Our findings were further validated by independent laboratory submissions in the Oncomine database, including Glück et al, 44 Richardson et al, 45 and Turashvili et al 46 breast data sets, all showing that AMPKα2 mRNA expression was consistently reduced in breast cancer compared to normal breast samples. In addition, Kim et al 47 recently described a comprehensive transcriptome analysis of gastric cancer using multiple analytical algorithms, demonstrating that the AMPKα2 isoform was uniquely suppressed in tumors compared to normal samples. This widespread phenomenon suggests that the observed impairment of AMPK activation in situ 27 may be due, at least in part, to the reduced levels of AMPKα2 expression.…”

Genetics and Molecular Pathogenesis of Gastric Adenocarcinoma

“…106 Investigators have also used RNA-sequencing data of GCs from different countries to identify the AMPK/HNF4α/Wnt5α pathway as a targetable oncogenic pathway in early-stage GC. 107,108 However, it should be noted that while transcriptomes are highly dynamic, almost all GC transcriptomic studies to date have relied upon analyzing GCs obtained at a single time-point, usually upon surgical resection. There is thus great interest in understanding gene expression (and other molecular) changes in GCs during temporal progression or treatment.…”

MicroRNA-29c mediates initiation of gastric carcinogenesis by directly targeting ITGB1

“…In comparison with microarray platforms, NGS-based sequencing technologies have several advantages, including massive parallel analysis of widely expressed miRNAs in the genome, quantification of absolute abundance of miRNAs, identification of miRNA sequence variations and discovery of novel miRNAs. Although few recent studies have attempted transcriptomic profiling in GC,11 12 to the best of our knowledge, none of the previous studies have used NGS-based platform for the discovery and validation of GC-specific miRNAs by analysing matched tumour and non-cancerous gastric tissues.…”