ShRNA-mediated knock-down of CXCL8 inhibits tumor growth in colorectal liver metastasis

Journal Article · Fri Jun 15 00:00:00 EDT 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.04.144· OSTI ID:23125184

Kumar, Abhishek ^[1]; Cherukumilli, Madhuri ^[2]; Mahmoudpour, Seyed Hamidreza ^[1]; Brand, Karsten ^[3]

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1. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg (Germany)
2. Molecular Medicine Partnetship Unit (DKFZ), Im Neuenheimer Feld 350, D-69120, Heidelberg (Germany)
3. Institute of Pathology, Im Neuenheimer Feld 220, 69120 Heidelberg (Germany)

Highlights: • Showed an up regulation of chemokines (1, 2, 3, 5 and 8) in the tumor invasion front compared to inner parts of the tumor in a xenograft model of colorectal liver metastasis. • Upregulation of CXCL8 in the invasion front of tumor cells is able to promote colorectal liver metastasis. • ShRNA mediated knockdown of CXCL8 in LS174T cells resulted in significantly decreased cell proliferation, migration and invasion in vitro and in a near complete reduction of tumor growth in vivo. • Results suggest an association between CXCL8 expression and progression of colorectal carcinoma and the development of colorectal liver metastases. • CXCL8 may serve as a potential therapeutic target for the treatment of colorectal liver metastasis. CXCL8 belongs to proinflammatory chemokines that are predominantly involved in neutrophil chemotaxis and degranulation. Several studies have suggested that secretion of CXCL8 from cancer cells have a profound effect on tumor microenvironment. In this study, in continuation to our previous work of understanding the global picture of invasion related genes in colorectal liver metastases, we clearly show an up-regulation of CXCL8 expression in the tumor cells at the invasion front as compared to the tumor cells in the inner parts of the tumor. Furthermore, ShRNA mediated down-regulation of CXCL8 resulted in inhibition of cell proliferation, viability and invasion in vitro and a near complete growth reduction of tumor in vivo. We showed that CXCL8 secreted by tumor cells at the invasion front were able to promote migration through angiogenesis by upregulating VEGFA and invasion via the AKT/GSK3β/β-catenin/MMP7 pathway by upregulating BCL-2 confirming the key role of CXCL8 during tumor progression.

• OSTI ID: 23125184
• Journal Information: Biochemical and Biophysical Research Communications, Vol. 500, Issue 3; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CARCINOMAS
CELL PROLIFERATION
LIVER
NEUTROPHILS
TUMOR CELLS