The 5-/12-lipoxygenase-BLT2 cascade induces elevated expression of c-Myc, thus mediating the proliferation and migration of KRAS mutant colorectal cancer cells

• Published in: Animal cells and systems Vol. 27; no. 1; pp. 403 - 412
• Main Authors: Park, Jaein, Jang, Jae-Hyun, Wei, Jun-Dong, Kim, Jae-Hong
• Format: Journal Article
• Language: English
• Published: Daejeon Taylor & Francis 11.12.2023; Taylor & Francis Ltd; Taylor & Francis Group; 한국통합생물학회
• Subjects: Arachidonate 12-lipoxygenase; BLT2; c-Myc protein; cadherins; Cancer; carcinogenesis; Cell growth; Cell migration; Cell proliferation; Colorectal cancer; Colorectal carcinoma; colorectal neoplasms; Cyclin D1; cyclins; death; E-cadherin; K-Ras protein; KRAS; Leukotriene B4 receptors; ligands; Lipoxygenase; Mutants; Myc; Myc protein; oncogenes; siRNA; Therapeutic targets; therapeutics; Tumorigenesis; Vimentin; 생물학
• ISSN: 1976-8354; 2151-2485; 2151-2485
• DOI: 10.1080/19768354.2023.2290031

Colorectal cancer (CRC) is the most common malignant tumor and one of the leading causes of cancer-related death worldwide. Oncogene KRAS is a commonly mutated in CRC and plays crucial roles in the colorectal tumorigenesis. Emerging evidence suggests that increased expression levels of c-Myc are critical for KRAS-mediated CRC progression. However, it is unclear exactly how c-Myc expression is regulated in CRC. In the present study, we found that blockade of 5/12-lipoxygenase (5/12-LO) or leukotriene B 4 receptor (BLT2) markedly reduced c-Myc expression in KRAS-mutant LOVO cells, while the control COLO 320DM cells were not affected. When the 5/12-LO products LTB 4 and 12(S)-HETE, ligands of BLT2, were added to LOVO cells, c-Myc expression levels were restored, together suggesting that '5/12-LO-BLT2 cascade' regulates c-Myc expression in KRAS-mutant CRC cells. We also observed that '5/12-LO-BLT2'-mediated c-Myc upregulation contributes to cell proliferation by regulating the expression of cyclin D1 in LOVO cells. Moreover, '5/12-LO-BLT2-cMyc' cascade regulates the expression of EMT-related proteins in KRAS-mutant CRC cells, and depletion of both c-Myc and BLT2 using siRNA significantly enhanced the level of E-cadherin and reduced the level of Vimentin in LOVO cells. Taken together, our findings suggest that the BLT2-linked cascade promotes KRAS-mutant CRC cell proliferation and migration through the elevated expression of c-Myc. Thus, our results suggest that BLT2 appears to be an effective therapeutic target for KRAS-mutant CRCs.