SPARC was overexpressed in human endometrial cancer stem-like cells and promoted migration activity.
OBJECTIVE
We previously demonstrated that side-population (SP) cells found in human endometrial cancer tissue have features of cancer stem cells (CSCs). Endometrial cancer SP cells show enhanced migration, the potential to differentiate into the mesenchymal cell lineage, and they are associated with the epithelial-mesenchymal transition (EMT). In this study, we analyzed the expression and function of a specific protein, SPARC (secreted protein acidic and rich in cysteine) which we found to be up-regulated in endometrial cancer.


METHODS
We performed microarray expression analysis to screen for up-regulated genes in CSCs using a set of RK12V-SP cells and -non-SP (NSP) cells. We used the MetaCore package to identify the Gene GO pathway MAPs associated with the up-regulated genes. Here, we investigated the expression and functions of SPARC, one of the genes up-regulated in endometrial CSCs. We established SPARC-overexpressing cells by transfecting endometrial cancer cells (Ishikawa cells [IK-SPARC cells]). We characterized these cells' growth rate, tumorigenicity, migration and invasion activity. The levels and locations of SPARC protein expression in Hec1SP cells-derived tumors and endometrial cancer tissues were examined by immunohistochemistry.


RESULTS
SPARC was detected by microarray expression analysis during screens for up-regulated genes in SP and NSP CSC. The level of SPARC expression was enhanced in Hec1 SP cells compared with that in Hec1 non-SP cells. SPARC enhanced fibronectin expression and promoted migration activity in IK cells. SPARC expression suppressed tumor growth but promoted formation of tumor stroma. SPARC was expressed in endometrial cancer tissues, in particular, poorly differentiated endometrioid adenocarcinoma, clear and serous adenocarcinoma,but not in normal endometrial tissue.


CONCLUSIONS
This is the first report of overexpression of SPARC in endometrial cancer stem-like cells. SPARC expression is associated with cell migration and stroma formation.
Department of Obstetrics and Gynecology, Faculty of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku 113-8431, Japan.
Nurismangul
N
Yusuf
Department of Obstetrics and Gynecology, Faculty of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku 113-8431, Japan.
Tetsunori
T
Inagaki
Department of Obstetrics and Gynecology, Faculty of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku 113-8431, Japan.
Soshi
S
Kusunoki
Department of Obstetrics and Gynecology, Faculty of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku 113-8431, Japan.
Hitomi
H
Okabe
Department of Obstetrics and Gynecology, Faculty of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku 113-8431, Japan.
Izumi
I
Yamada
Department of Obstetrics and Gynecology, Faculty of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku 113-8431, Japan.
Akemi
A
Matsumoto
Department of Obstetrics and Gynecology, Faculty of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku 113-8431, Japan.
Yasuhisa
Y
Terao
Department of Obstetrics and Gynecology, Faculty of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku 113-8431, Japan.
Satoru
S
Takeda
Department of Obstetrics and Gynecology, Faculty of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku 113-8431, Japan; Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: kkato@med.kyushu-u.ac.jp.
Kiyoko
K
Kato
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D015676:Osteonectin / Q000096:biosynthesis* / Q000235:genetics*
D015676:Osteonectin; C577241:SPARC protein, human
CSCs; Cell migration; EMT; Endometrial cancer; SPARC