Abstract
CD44 plays a role in the progression of tumors and is expressed in cancer stem cells (CSCs). However, the mechanisms underlying the crosstalk of CD44 with stemness genes in CSC maintenance remains unclear. In this study, we demonstrated how the cleaved intracellular domain of CD44 (CD44ICD) activates stemness factors such as Nanog, Sox2 and Oct4, and contributes to the tumorigenesis of breast cancer. We have found that the overexpression of CD44ICD increased mammosphere formation in breast cancer cells. Treatment with a γ-secretase inhibitor (GSI), which blocks the cleavage of CD44ICD, interfered with mammosphere formation. Interestingly, CD44ICD decreased the expression levels and nuclear localization of stemness factors, but overexpression of CD44ICD reversed these effects. In addition, we showed that nuclear localization of CD44ICD is important for transcriptional activation of the stemness factors. Furthermore, CD44ICD-overexpressed cells exhibited strong tumorigenecity and greater metastatic potential than did the control cells or CD44-depleted cells in vivo in mice models. Taken together, it was supposed that CD44 promotes tumorigenesis through the interaction and nuclear-translocation of its intracellular domain and stemness factors. We suggest that the prevention of cleavage and nuclear-translocation of CD44ICD is a potential target in treating breast cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 8709-8721 |
| Number of pages | 13 |
| Journal | Oncotarget |
| Volume | 6 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2015 Jan 1 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Oncology
Cite this
}
Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer. / Cho, Yunhee; Lee, Hyun Woo; Kang, Hyeok Gu; Kim, Hye Young; Kim, Seok Jun; Chun, Kyung Hee.
In: Oncotarget, Vol. 6, No. 11, 01.01.2015, p. 8709-8721.Research output: Contribution to journal › Article
TY - JOUR
T1 - Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer
AU - Cho, Yunhee
AU - Lee, Hyun Woo
AU - Kang, Hyeok Gu
AU - Kim, Hye Young
AU - Kim, Seok Jun
AU - Chun, Kyung Hee
PY - 2015/1/1
Y1 - 2015/1/1
N2 - CD44 plays a role in the progression of tumors and is expressed in cancer stem cells (CSCs). However, the mechanisms underlying the crosstalk of CD44 with stemness genes in CSC maintenance remains unclear. In this study, we demonstrated how the cleaved intracellular domain of CD44 (CD44ICD) activates stemness factors such as Nanog, Sox2 and Oct4, and contributes to the tumorigenesis of breast cancer. We have found that the overexpression of CD44ICD increased mammosphere formation in breast cancer cells. Treatment with a γ-secretase inhibitor (GSI), which blocks the cleavage of CD44ICD, interfered with mammosphere formation. Interestingly, CD44ICD decreased the expression levels and nuclear localization of stemness factors, but overexpression of CD44ICD reversed these effects. In addition, we showed that nuclear localization of CD44ICD is important for transcriptional activation of the stemness factors. Furthermore, CD44ICD-overexpressed cells exhibited strong tumorigenecity and greater metastatic potential than did the control cells or CD44-depleted cells in vivo in mice models. Taken together, it was supposed that CD44 promotes tumorigenesis through the interaction and nuclear-translocation of its intracellular domain and stemness factors. We suggest that the prevention of cleavage and nuclear-translocation of CD44ICD is a potential target in treating breast cancer.
AB - CD44 plays a role in the progression of tumors and is expressed in cancer stem cells (CSCs). However, the mechanisms underlying the crosstalk of CD44 with stemness genes in CSC maintenance remains unclear. In this study, we demonstrated how the cleaved intracellular domain of CD44 (CD44ICD) activates stemness factors such as Nanog, Sox2 and Oct4, and contributes to the tumorigenesis of breast cancer. We have found that the overexpression of CD44ICD increased mammosphere formation in breast cancer cells. Treatment with a γ-secretase inhibitor (GSI), which blocks the cleavage of CD44ICD, interfered with mammosphere formation. Interestingly, CD44ICD decreased the expression levels and nuclear localization of stemness factors, but overexpression of CD44ICD reversed these effects. In addition, we showed that nuclear localization of CD44ICD is important for transcriptional activation of the stemness factors. Furthermore, CD44ICD-overexpressed cells exhibited strong tumorigenecity and greater metastatic potential than did the control cells or CD44-depleted cells in vivo in mice models. Taken together, it was supposed that CD44 promotes tumorigenesis through the interaction and nuclear-translocation of its intracellular domain and stemness factors. We suggest that the prevention of cleavage and nuclear-translocation of CD44ICD is a potential target in treating breast cancer.
UR - http://www.scopus.com/inward/record.url?scp=84928717089&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84928717089&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.3325
DO - 10.18632/oncotarget.3325
M3 - Article
C2 - 25909162
AN - SCOPUS:84928717089
VL - 6
SP - 8709
EP - 8721
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 11
ER -