Reconstitution of secreted frizzled-related protein 1 suppresses tumor growth and lung metastasis in an orthotopic model of hepatocellular carcinoma.
BACKGROUND
Secreted Frizzled-related protein 1 (sFRP1) is frequently silenced in many types of cancer, including hepatocellular carcinoma (HCC), leading to aberrant activation of Wnt signaling and thereby facilitating tumor development. In this study, we aimed to investigate whether restoration of sFRP1 affected HCC growth and metastasis.


METHODS
We generated stable cell lines overexpressing sFRP1 in MHCC97-H cells, which naturally do not express detectable sFRP1 messenger RNA (mRNA) and have high metastatic properties. The effects of sFRP1 reexpression on tumor growth and metastasis were assessed in vitro and in vivo. It was also tested whether β-catenin signaling mediated the function of sFRP1 in tumor progression.


RESULTS
Overexpression of sFRP1 substantially diminished the proliferation and invasion potentials of MHCC97-H cells. Furthermore, sFRP1 expression significantly inhibited MHCC97-H xenograft growth and metastasis in vivo, which was accompanied by decreased angiogenesis and increased tumor cell apoptosis. Moreover, sFRP1 overexpression caused less expression of β-catenin and its downstream effector genes cyclin D1 and matrix metalloproteinase (MMP)-2.


CONCLUSIONS
Together these findings demonstrate that sFRP1 reconstitution suppresses tumor growth, angiogenesis, and metastasis in MHCC97-H xenografts, which may be associated with inactivation of β-catenin signaling, thus providing a possible therapeutic strategy against HCC.
Jiang
Gui-Xing
GX
Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, 150086, Harbin, China.
Liu
Wei
W
Cui
Yun-Fu
YF
Zhong
Xiang-Yu
XY
Tai
Sheng
S
Wang
Zhi-Dong
ZD
Shi
Yu-Guang
YG
Li
Chun-Long
CL
Zhao
Shi-Yong
SY
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000503:physiopathology / Q000556:secondary*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000503:physiopathology / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000099274:Frizzled-Related Proteins
D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; C495268:Ctnnb1 protein, rat