The CCL6 chemokine is differentially regulated by c-Myc and L-Myc, and promotes tumorigenesis and metastasis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2003-06, Vol.63 (11), p.2923-2932
• Main Authors: FENGHUA YI, JAFFE, Ronald, PROCHOWNIK, Edward V
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - genetics; Apoptosis - physiology; Biological and medical sciences; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Division - drug effects; Cell Division - physiology; Cell physiology; Cell Survival - genetics; Cell Survival - physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chemokines, CC - biosynthesis; Chemokines, CC - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Mice; Molecular and cellular biology; Neoplasm Metastasis; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - physiology; Transcription, Genetic; Transfection; Up-Regulation
• ISSN: 0008-5472; 1538-7445

The CCL6 chemokine gene was identified as a direct positive target of the L-Myc oncoprotein in interleukin 3-dependent 32D myeloid cells. A mutant form of c-Myc, lacking a region of the NH(2)-terminal domain necessary for transcriptional repression (c-MycDeltaMBII), also up-regulated CCL6. Chromatin immunoprecipitation showed that L-Myc, c-MycDeltaMBII, and full-length c-Myc all bound the CCL6 promoter, although the latter was inactive in transcriptional up-regulation. Exogenously added CCL6 induced marked apoptosis in some cell types. However, in 32D cells, the coexpression of c-Myc and CCL6 abrogated interleukin 3 dependence and produced a highly leukemogenic phenotype. In two solid tumor models, CCL6 overexpression also accelerated tumor growth, and/or enhanced local and metastatic spread in association with marked apoptosis of the tumor capsule and adjacent normal tissues. Our results show that CCL6 can be either a positive or negative target for Myc oncoproteins. The chemokine may alter tumor behavior by relieving its growth factor dependency and by promoting invasiveness as a result of local tissue apoptosis.