Abstract
A proliferation-inducing ligand (APRIL) is highly expressed in colorectal cancer (CRC) tissues and cell lines. However, the biological functions and precise signals elicited by APRIL in CRC have not been fully understood. Here, we used small interfering RNA to selectively deplete APRIL and to determine its tumorigenic effects in a CRC cell line SW480 both in vitro and in vivo. Knockdown of APRIL in SW480 cells was associated with modulation of cell proliferation as well as reduction of cell migration and invasion in vitro. Moreover APRIL-knockdown SW480 cells displayed markedly inhibited tumor growth and decreased metastasis to the liver in immunodeficient mice upon subcutaneous injection. Importantly, we observed that downregulation of APRIL in SW480 cells resulted in greatly decreased activity of phosphoinositide 3-kinase (PI3K)/Akt pathway. In addition, we observed that recombinant human APRIL mediated activation of the PI3K/Akt pathway in CRC cells resulting in induced expression of important cell cycle proteins and matrix metalloproteinases in a PI3K/Akt dependent manner. This was concurrent with marked cell growth viability as well as increased cell migration and invasion. Together, these compelling data suggest that APRIL-induced tumorigenesis and metastasis of CRC cells may be accomplished through activation of the PI3K/Akt pathway. These findings may lead to a better understanding of the biological effects of APRIL and may provide clues for identifying novel therapeutic and preventive molecular markers for CRC.
Highlights
Colorectal cancer (CRC) is a major public health problem in the United States and globally
A proliferation-inducing ligand (APRIL) mRNA was detected at relatively higher levels in a variety of human CRC cell lines compared with human umbilical vein endothelial cells, the levels of APRIL differed
To reduce APRIL expression, we developed two short hairpin RNAs termed sh637 and sh1750 [17] which were directed against the human APRIL gene and caused significant reduction of APRIL expression compared with nontargeting control transfected and nontransfected cells
Summary
Colorectal cancer (CRC) is a major public health problem in the United States and globally. In the United States, it is the third most common cancer and the third leading cause of cancer mortality if men and women are considered separately [1]. Occurrence of metastases due to tumor progression is the cause of the majority of cancer-related deaths. The PI3K signaling pathway plays an essential role in cancer cell proliferation, survival, metabolism, motility and invasion. It is frequently deregulated in CRC cells, making it an attractive therapeutic target [2,3,4]. Upregulated cytokines, growth factors, and their receptors observed in CRC cells via PI3K probably represent a principal contribution to tumorigenesis
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