High expression of protein phosphatase 4 is associated with the aggressive malignant behavior of colorectal carcinoma.
BACKGROUND
Recent evidence suggests an important role of protein phosphatase 4 (PP4C) in the progression of several cancers, including breast cancer, lung cancer and pancreatic ductal adenocarcinoma. However, the contribution of PP4C to colorectal carcinoma (CRC) remains elusive.


METHODS
The expression of PP4C in CRC tissues compared with matched non-tumor tissues and CRC cells was detected using quantitative RT-PCR, immunohistochemistry and western blotting assays. Through univariate and Kaplan-Meier analysis, we correlated the PP4C expression with clinicopathological features and patient survival. A series of experiments, including cell proliferation, lentiviral infection, cell invasion and MMP gelatinase activity assays, were performed to investigate the underlying mechanisms. Through further experiments, tumor growth and metastasis were evaluated in vivo using a xenogenous subcutaneously implant model and a tail vein metastasis model.


RESULTS
In the present study, we found that PP4C expression is frequently increased in human CRC and that the upregulation of PP4C correlates with a more invasive tumor phenotype and poor prognosis. The ectopic expression of PP4C promoted CRC cell proliferation, migration and invasion in vitro and tumor growth and lung metastasis in vivo. Silencing the expression of PP4C resulted in the inhibition of cell proliferation and invasion. Further investigations showed that phosphorylated Akt (p-AKT) is required for the PP4C-mediated upregulation of MMP-2 and MMP-9, which promotes cell invasion.


CONCLUSIONS
Our data suggested a potential role of PP4C in tumor progression and provided novel insights into the mechanism of how this factor positively regulated cell proliferation and invasion in CRC cells.
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. lxx1149@163.com.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. lxx1149@163.com.
Xinxiang
X
Li
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. LLKNIGHT115@163.com.
Lei
L
Liang
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. hly_981@163.com.
Liyong
L
Huang
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. yamimikaka@163.com.
Xiaoji
X
Ma
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. davidleehero@126.com.
Dawei
D
Li
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. caisanjuncsj@163.com.
Sanjun
S
Cai
D000328:Adult; D000818:Animals; D063646:Carcinogenesis / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008819:Mice, Nude; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D016019:Survival Analysis; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9