Nestin suppression attenuates invasive potential of endometrial cancer cells by downregulating TGF-β signaling pathway.
Nestin, an intermediate filament protein and a stem cell marker is expressed in several tumors. Until recently, little was known about the expression levels and the role of Nestin in endometrial cancer. Compared to the immortalized endometrial epithelial cell line EM-E6/E7-TERT, endometrial cancer cell lines express high to moderate levels of Nestin. Furthermore, endometrial tumors and tumor cell lines have a cancer stem-like cell subpopulation expressing CD133. Among the cancer lines, AN3CA and KLE cells exhibited both a significantly higher number of CD133+ cells and expressed Nestin at higher levels than Ishikawa cells. Knockdown of Nestin in AN3CA and KLE increased cells in G0/G1 phase of the cell cycle, whereas overexpression in Ishikawa decreased cells in G0/G1 phase and increased cells in S-phase. Nestin knockdown cells showed increased p21, p27, and PNCA levels and decreased expression of cyclin-D1 and D3. In contrast, Nestin overexpression revealed an inverse expression pattern of cell cycle regulatory proteins. Nestin knockdown inhibited cancer cell growth and invasive potential by downregulating TGF-β signaling components, MMP-2, MMP-9, vimentin, SNAIL, SLUG, Twist, N-cadherin, and upregulating the epithelial cell marker E-cadherin whereas the opposite was observed with Nestin overexpressing Ishikawa cells. Nestin knockdown also inhibited, while overexpression promoted invadopodia formation and pFAK expression. Knockdown of Nestin significantly reduced tumor volume in vivo. Finally, progesterone inhibited Nestin expression in endometrial cancer cells. These results suggest that Nestin can be a therapeutic target for cancer treatment.
Uniformed Services University, Department of Obstetrics and Gynecology, Bethesda, MD 20814, USA.
Amber A
AA
Bokhari
Uniformed Services University, Department of Obstetrics and Gynecology, Bethesda, MD 20814, USA.
Tabari M
TM
Baker
Uniformed Services University, Department of Obstetrics and Gynecology, Bethesda, MD 20814, USA.
Batsukh
B
Dorjbal
Uniformed Services University, Department of Obstetrics and Gynecology, Bethesda, MD 20814, USA.
Sana
S
Waheed
American College of Obstetricians and Gynecologists, Washington, DC 20024, USA.
Christopher M
CM
Zahn
Uniformed Services University, Department of Obstetrics and Gynecology, Bethesda, MD 20814, USA.|Women's Health Integrated Research Center at Inova Health System, Department of Defense Gynecologic Cancer Center of Excellence, Annandale, VA 22003, USA.|John P. Murtha Cancer Center at Water Reed National Military Medical Center, Bethesda, MD 20889, USA.
Chad A
CA
Hamilton
Women's Health Integrated Research Center at Inova Health System, Department of Defense Gynecologic Cancer Center of Excellence, Annandale, VA 22003, USA.|John P. Murtha Cancer Center at Water Reed National Military Medical Center, Bethesda, MD 20889, USA.|Inova Fairfax Hospital, Department of Obstetrics and Gynecology, Falls Church, VA 22042, USA.
G Larry
GL
Maxwell
Uniformed Services University, Department of Obstetrics and Gynecology, Bethesda, MD 20814, USA.|John P. Murtha Cancer Center at Water Reed National Military Medical Center, Bethesda, MD 20889, USA.|Uniformed Services University, Department of Molecular and Cell Biology, Bethesda, MD 20814, USA.
Viqar
V
Syed
D015820:Cadherins / Q000032:analysis; D045744:Cell Line, Tumor; D015536:Down-Regulation; D016889:Endometrial Neoplasms / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D009361:Neoplasm Invasiveness; D064231:Nestin / Q000502:physiology*; D011374:Progesterone / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D015820:Cadherins; D064231:Nestin; D016212:Transforming Growth Factor beta; D011374:Progesterone
angiogenesis; cell proliferation; epithelial-mesenchymal-transition; matrix metalloproteinases; progesterone