Abstract
The nuclear receptor coactivator 5 (NCOA5) displays both coactivator and corepressor functions. Previous studies showed that alteration of NCOA5 participates in carcinogenesis and progression. However, its roles in colorectal cancer (CRC) remain unknown. Herein, we demonstrated that expression of NCOA5 in human CRC tissues was notably higher than that in adjacent tissues, which significantly correlated with clinicopathological features such as length of tumor, regional lymph node staging and cancer staging. Knockdown of NCOA5 markedly suppressed proliferation, migration and invasion of SW620 high malignant CRC cells. Silencing of NCOA5 also inhibited in vivo growth of SW620 CRC subcutaneously xenografted tumors in athymic BALB/c nude mice. Meanwhile, Overexpression of NCOA5 facilitated these processes in SW480 low malignant CRC cells. Furthermore, knockdown of NCOA5 induced cell cycle G1 phase arrest in SW620 cells, whereas overexpression of NCOA5 promoted G1 to S phase transition in SW480 cells. Mechanistic studies revealed that NCOA5 upregulated phospho-protein kinase B (p-PKB/AKT), Cyclin D1 and matrix metalloproteinase 9 (MMP9) as well as downregulated P27 in CRC cells. Notably, PI3K inhibitor LY294002 obviously attenuated the effects of NCOA5 on p-AKT, Cyclin D1, P27 and MMP9. Moreover, LY294002 and knockdown of Cyclin D1 or MMP9 remarkably blocked the tumor-promoting activity of NCOA5. Collectively, NCOA5 promoted CRC cell proliferation, migration and invasion by upregulating Cyclin D1 and MMP9 while downregulating P27 to a great extent via activating PI3K/AKT signaling pathway. These findings suggested that NCOA5 exhibits an oncogenic effect in human CRC and represents a novel therapeutic target for CRC.
Highlights
Colorectal cancer (CRC) is the second most commonly diagnosed malignancy in women and the third in men worldwide, which is one of the leading causes of cancer-related mortality [1]
The present study provided the first compelling evidence that (i) nuclear receptor coactivator 5 (NCOA5) is highly expressed in human colorectal cancer (CRC) tissues; (ii) NCOA5 has a significant positive correlation with length of tumor, regional lymph node staging and cancer staging of CRC patients; and (iii) NCOA5 promotes proliferation, migration and invasion of CRC cells by upregulating Cyclin D1 and matrix metalloproteinase 9 (MMP9) as well as downregulating P27 through activating PI3K/AKT pathway
These findings suggested that the antitumor or protumor effect of NCOA5 in human cancers may be dependent on tissue type
Summary
Colorectal cancer (CRC) is the second most commonly diagnosed malignancy in women and the third in men worldwide, which is one of the leading causes of cancer-related mortality [1]. The prognosis and overall survival of CRC still remains poor due to late diagnosis and metastasis [2]. Accumulating alteration of oncogenes and tumor suppressor genes as well as dysregulated signaling pathways are crucial for tumorgenesis and progression of CRC. Recent advances in molecular biology have led to an increased knowledge of mechanisms responsible for CRC, only a limited number of critical molecules those have clinicopathological significance in CRC have been discovered.
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