Shouhua Zhang1, Juhua Xiao2, Yong Chai1, Zhengdong Hong3, Zhiqiang Liu1, Rongfa Yuan3, Zhipeng Luo4, Xin Zhou2, Don Eliseo Lucero-Prisno5, Kai Huang6. 1. Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, 330006, China. 2. Department of Ultrasound, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, China. 3. Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China. 4. Department of Gastrointestinal Surgery, Jiangxi Provincial Cancer Hospital, No. 519, Beijing East Road, Nanchang, 330029, Jiangxi, China. 5. Department of Public Health, Xi'an Jiaotong-Liverpool University, Suzhou, 215123, China. 6. Department of Gastrointestinal Surgery, Jiangxi Provincial Cancer Hospital, No. 519, Beijing East Road, Nanchang, 330029, Jiangxi, China. huang_k79@outlook.com.
Abstract
BACKGROUND: Elevated expression of matrix metalloproteinases (MMPs) is correlated with invasion and metastasis of colorectal cancer (CRC). Recently, a previous study has suggested that speckle-type POZ protein (SPOP) could inhibit cancer cell proliferation and migration through down-regulation of MMP2 and MMP7, with a mechanism remaining unknown. AIM: In this study, we, by using both CRC cells and normal colorectal cells, aimed to investigate the causal relationship between SPOP and MMP2, as well as the potential signaling pathways. METHODS: The causal relationship between SPOP and MMP2 was determined by both RT-PCR and Western blot in cells with SPOP expression or siRNA interference. The signaling pathway involved in MMP2 down-regulation by SPOP was subsequently identified by determination on the expression and phosphorylation of key signaling pathway proteins. Transcription factor involving in this MMP2 regulation was identified by determination on expression, phosphorylation, and nuclear translocation of key transcription factors. RESULTS: SPOP overexpression could significantly decrease MMP2 expression, while the knockdown of SPOP, in contrast, resulted in enhanced MMP2 level. Measurement of expression and phosphorylation of key signaling pathway proteins revealed that SPOP could inhibit PI3K and p-Akt level. Further tests on transcription factors showed that SPOP could inhibit SP1 phosphorylation and nuclear translocation. CONCLUSIONS: SPOP could down-regulate MMP2 expression in CRC, and this regulation is mediated by inhibiting SP1 phosphorylation and nuclear translocation through PI3K/Akt signaling pathway. Our findings in this study provide understanding of MMP2 regulation in CRC and may also shed lights on the development of anti-CRC treatments.
BACKGROUND: Elevated expression of matrix metalloproteinases (MMPs) is correlated with invasion and metastasis of colorectal cancer (CRC). Recently, a previous study has suggested that speckle-type POZ protein (SPOP) could inhibit cancer cell proliferation and migration through down-regulation of MMP2 and MMP7, with a mechanism remaining unknown. AIM: In this study, we, by using both CRC cells and normal colorectal cells, aimed to investigate the causal relationship between SPOP and MMP2, as well as the potential signaling pathways. METHODS: The causal relationship between SPOP and MMP2 was determined by both RT-PCR and Western blot in cells with SPOP expression or siRNA interference. The signaling pathway involved in MMP2 down-regulation by SPOP was subsequently identified by determination on the expression and phosphorylation of key signaling pathway proteins. Transcription factor involving in this MMP2 regulation was identified by determination on expression, phosphorylation, and nuclear translocation of key transcription factors. RESULTS: SPOP overexpression could significantly decrease MMP2 expression, while the knockdown of SPOP, in contrast, resulted in enhanced MMP2 level. Measurement of expression and phosphorylation of key signaling pathway proteins revealed that SPOP could inhibit PI3K and p-Akt level. Further tests on transcription factors showed that SPOP could inhibit SP1 phosphorylation and nuclear translocation. CONCLUSIONS: SPOP could down-regulate MMP2 expression in CRC, and this regulation is mediated by inhibiting SP1 phosphorylation and nuclear translocation through PI3K/Akt signaling pathway. Our findings in this study provide understanding of MMP2 regulation in CRC and may also shed lights on the development of anti-CRC treatments.
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