title: HMGA1 drives metabolic reprogramming of intestinal epithelium during hyperproliferation, polyposis, and colorectal carcinogenesis.
abstract: Although significant progress has been made in the diagnosis and treatment of colorectal cancer (CRC), it remains a leading cause of cancer death worldwide. Early identification and removal of polyps that may progress to overt CRC is the cornerstone of CRC prevention. Expression of the High Mobility Group A1 (HMGA1) gene is significantly elevated in CRCs as compared with adjacent, nonmalignant tissues. We investigated metabolic aberrations induced by HMGA1 overexpression in small intestinal and colonic epithelium using traveling wave ion mobility mass spectrometry (TWIMMS) in a transgenic model in which murine Hmga1 was misexpressed in colonic epithelium. To determine if these Hmga1-induced metabolic alterations in mice were relevant to human colorectal carcinogenesis, we also investigated tumors from patients with CRC and matched, adjacent, nonmalignant tissues. Multivariate statistical methods and manual comparisons were used to identify metabolites specific to Hmga1 and CRC. Statistical modeling of data revealed distinct metabolic patterns in Hmga1 transgenics and human CRC samples as compared with the control tissues. We discovered that 13 metabolites were specific for Hmga1 in murine intestinal epithelium and also found in human CRC. Several of these metabolites function in fatty acid metabolism and membrane composition. Although further validation is needed, our results suggest that high levels of HMGA1 protein drive metabolic alterations that contribute to CRC pathogenesis through fatty acid synthesis. These metabolites could serve as potential biomarkers or therapeutic targets.
authors: Department of Chemistry, Washington State University , 100 Dairy Road, Pullman, Washington 99164, United States.
authors: Michael D
authors: MD
authors: Williams
authors: Xing
authors: X
authors: Zhang
authors: Amy S
authors: AS
authors: Belton
authors: Lingling
authors: L
authors: Xian
authors: Tait
authors: T
authors: Huso
authors: Jeong-Jin
authors: JJ
authors: Park
authors: William F
authors: WF
authors: Siems
authors: David R
authors: DR
authors: Gang
authors: Linda M S
authors: LM
authors: Resar
authors: Raymond
authors: R
authors: Reeves
authors: Herbert H
authors: HH
authors: Hill
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000503:physiopathology*; D049109:Cell Proliferation / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D025741:HMGA1a Protein / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D053719:Tandem Mass Spectrometry
chemical_list: D025741:HMGA1a Protein
keywords: HMGA1; biomarker discovery; cancer metabolomics ion mobility mass spectrometry; colorectal cancer; ion mobility; mass spectrometry; metabolomics