Abstract
The β4-integrin subunit has been implicated in development and progression of several epithelial tumor types. However, its role in metastases of colorectal cancer (CRC) remains elusive. To study CRC metastasis, we generated a highly invasive, metastatic cell line MC38-LM10 (LM10) by passaging mouse CRC MC38 cells ten times, using a splenic injection model of liver metastasis. Affymetrix microarray analyses of LM10 and MC38 cell lines and their corresponding liver metastases generated a gene signature for CRC metastasis. This signature shows strong upregulation of β4-integrin in LM10 cells and corresponding metastases. Upregulation of β4-integrin in highly aggressive LM10 cells is associated with increased migration, invasion, and liver metastases. Furthermore, stable knockdown of β4-integrin in human CRC SW620 cells reduces Bcl-2 expression, increases apoptosis, and decreases invasion, tumorigenicity, and liver metastasis, thus resulting in significantly increased survival of mice (hazard ratio = 0.32, 95% confidence interval = 0.15-0.66, P<0.01). Patients with CRC tumors display higher β4-integrin levels in stages 1-4 and significantly lower survival rate. Collectively, β4-integrin plays a critical role in CRC progression, invasion, and metastasis, suggesting that it could be a potential therapeutic target for CRC patients.
Highlights
Colorectal cancer (CRC) represents the second most frequent type of cancer-related deaths in the United States [1]
MC38-Luc cells were injected into the spleens of C57BL/6 mice and three weeks later, mice were sacrificed, liver metastases were harvested, and the cell line was established by neomycin selection
We found that LM10 cells exhibited a 2.3-fold increase in cell migration compared with MC38 cells (Wilcoxon Rank Sum test, p
Summary
Colorectal cancer (CRC) represents the second most frequent type of cancer-related deaths in the United States [1]. Integrins are transmembrane glycoproteins and are an important family of heterodimeric cell adhesion receptors They have been shown to be critical in www.impactjournals.com/oncotarget controlling cell-cell and cell-matrix interactions, and regulate a variety of cellular functions crucial to the initiation, progression, and metastasis of solid tumors [4, 5]. Β4-integrin contains a long cytoplasmic domain (1017 amino acid), which does not share homology with other known mammalian integrins [8] This large and structurally-unique cytoplasmic domain of β4-integrin associates with cytoskeletal elements and is involved in cellular signaling functions [9, 10]. Studies have shown that β4-integrin can activate Ras and PI3K signaling pathways [5, 15]
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