COLUMBUS, Ohio - A new study identifies a molecule that is a probable driving force in colorectal cancer and suggests that the molecule could be an important target for colorectal cancer treatment and a valuable biomarker of tumor progression.
The study of microRNA-135b (miR-135b) in two animal models and human tumors was published in the journal Cancer Cell and was led by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) and at the University of Glasgow in the United Kingdom.
The researchers demonstrate that miR-135b is present at abnormally high levels in both mouse and human colorectal (CRC) tumors. The overexpression can be induced by the mutations in either well-known oncogenes or tumor-suppressor genes that frequently occur in CRC, the researchers say.
"We found that miR-135b is up-regulated in both sporadic and inflammatory bowel disease-associated colorectal cancer, and that its up-regulation is associated with tumor stage and poor clinical outcome," says principal investigator Carlo M. Croce, MD, chair of molecular virology, immunology and medical genetics, and director of Human Cancer Genetics at Ohio State and the OSUCCC - James.
"Our findings provide proof-of-principle that anti-miR-135b has significant therapeutic potential in colorectal cancer treatment," says Croce, who is also the John W. Wolfe Chair in Human Cancer Genetics.
For this study, Croce and his collaborators used a CRC mouse model based on loss of a tumor suppressor and a model based on inflammation and oncogene activation; human tumors from a cohort of sporadic CRC and inflammatory-bowel-disease associated CRC; human and animal cell lines and data from The Cancer Genome Atlas.
Key findings included:
- MiR-135b up-regulation occurs in both sporadic and inflammatory bowel disease-associated CRC, and it is associated with tumor stage and poor clinical outcome;
- Loss of the APC gene, deregulation of the PTEN/PI3K pathway and over-expression of the SRC oncogene all trigger miR-135b over-expression;
- Artificial miR-135b over-expression increases cell proliferation and reduces apoptosis, as occurs with APC loss or PI3K or SRC activation.
- Delivering anti-miR-135b in an inflammation-related CRC mouse model affected proliferation and apoptosis, resulting in reduced tumor number and size.
Funding from the National Institutes of Health (grants U01 CA152758, RC2 CA148302, 1R01 CA078230, AI043477, DK035108, K99-DK088589), the Kimmel Cancer Foundation Translational Scholar Award and Glasgow University Start-Up funds, the AACR, the Crohn's and Colitis Foundation of America supported this research.
Other researchers involved in this study were Pierluigi Gasparini, Francesca Lovat, Alessio Paone, Luciano Cascione, Khlea M. Sumani, Stefania Carasi, Hansjuerg Alder, Gerard J Nuovo, Wendy Frankel, Joanna Groden, The Ohio State University; Muller Fabbri, Children's Hospital Los Angeles; Nicola Valeri, Chiara Braconi, Andrea Lampis, Viola Paulus-Hock, University of Glasgow, Glasgow, United Kingdom (UK); Claudio Murgia, Rachel A Ridgway, Julia Cordero, Owen J Sansom, Beatson Institute for Cancer Research, Glasgow, UK; Jonathan R. Hart, Lynn Ueno, The Scripps Research Institute; Sergei I. Grivennikov, Peter K Vogt, Michael Karin, University of California San Diego; Angelo Veronese, Aging Research Center G. d'Annunzio University Foundation, Chieti, Italy; Mary P Moyer,
INCELL Corporation; and Massimo Rugge, Matteo Fassan, University of Padova, Italy.
The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 228-bed adult patient-care component, The James is a "Top Hospital" as named by the Leapfrog Group and one of the top cancer hospitals in the nation as ranked by U.S.News & World Report.