Human cytomegalovirus infection enhances 5-lipoxygenase and cycloxygenase-2 expression in colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the most common and fatal types of cancer. Inflammation promotes CRC development, however, the underlying etiological factors are unknown. Human cytomegalovirus (HCMV), a virus that induces inflammation and other cancer hallmarks, has been detected in several types of malignancy, including CRC. The present study investigated whether HCMV infection was associated with expression of the pro-inflammatory enzymes 5-lipoxygenase (5-LO) and cyclooxygenase-2 (COX-2) and other molecular, genetic and clinicopathological CRC features. The present study assessed 146 individual paraffin-embedded CRC tissue microarray (TMA) cores already characterized for TP53 and KRAS mutations, microsatellite instability (MSI) status, Ki-67 index and EGFR by immunohistochemistry (IHC). The cores were further analyzed by IHC for the expression of two HCMV proteins (Immediate Early, IE and pp65) and the inflammatory markers 5-LO and COX-2. The CRC cell lines Caco-2 and LS-174T were infected with HCMV strain VR1814, treated with antiviral drug ganciclovir (GCV) and/or anti-inflammatory drug celecoxib (CCX) and analyzed by reverse transcription-quantitative PCR and immunofluorescence for 5-LO, COX-2, IE and pp65 transcripts and proteins. HCMV IE and pp65 proteins were detected in ~90% of the CRC cases tested; this was correlated with COX-2, 5-LO and KI-67 expression, but not with EGFR immunostaining, TP53 and KRAS mutations or MSI status. In vitro, HCMV infection upregulated 5-LO and COX-2 transcript and proteins in both Caco-2 and LS-174T cells and enhanced cell proliferation as determined by MTT assay. Treatment with GCV and CCX significantly decreased the transcript levels of COX-2, 5-LO, HCMV IE and pp65 in infected cells. HCMV was widely expressed in CRC and may promote inflammation and serve as a potential new target for CRC therapy.