TY - JOUR
T1 - GATA3 as a master regulator for interactions of tumor-associated macrophages with high-grade serous ovarian carcinoma
AU - El-Arabey, Amr Ahmed
AU - Denizli, Merve
AU - Kanlikilicer, Pinar
AU - Bayraktar, Recep
AU - Ivan, Cristina
AU - Rashed, Mohammed
AU - Kabil, Nashwa
AU - Ozpolat, Bulent
AU - Calin, George A.
AU - Salama, Salama Abdu
AU - Abd-Allah, Adel Rashad
AU - Sood, Anil K.
AU - Lopez-Berestein, Gabriel
N1 - Funding Information:
This study was funded by the NIH Common Fund (UH2TR000943)- USA through the Office of Strategic Coordination/Office of the NIH Director to Gabriel Lopez-Berestein, Anil K. Sood and by the MD Anderson Cancer Center Center support grant (P30CA016672)-USA to Anil K. Sood and by Center for RNA Interference, Non-Coding RNA Interference, Non-Coding RNA, USA to Anil K. Sood, Gabriel Lopez-Berestein and by Ministry of Higher Education, Cultural Affairs, and Mission Sector, Joint-Supervision Program, EGYPT to Amr Ahmed El-Arabey.
Funding Information:
This study was funded by the NIH Common Fund ( UH2TR000943 )- USA through the Office of Strategic Coordination/Office of the NIH Director to Gabriel Lopez-Berestein, Anil K. Sood and by the MD Anderson Cancer Center Center support grant ( P30CA016672 )-USA to Anil K. Sood and by Center for RNA Interference, Non-Coding RNA Interference, Non-Coding RNA, USA to Anil K. Sood, Gabriel Lopez-Berestein and by Ministry of Higher Education, Cultural Affairs, and Mission Sector , Joint-Supervision Program, EGYPT to Amr Ahmed El-Arabey.
Publisher Copyright:
© 2020
PY - 2020/4
Y1 - 2020/4
N2 - High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic cancer. Emerging evidence suggests that tumor-associated macrophages (TAMs) play an immunosuppressive role in the tumor microenvironment and promote tumor growth, angiogenesis, and metastasis in ovarian cancer. Therefore, targeting TAMs in patients with ovarian cancer is an appealing strategy; however, all trials to date have failed. To improve the efficacy of this approach, we sought to elucidate the underlying mechanisms of the role of TAMs in ovarian cancer. We found that the developmental transcription factor GATA3 was highly expressed in HGSOC cell lines but not in the fallopian tube, which is the main origin of HGSOC. GATA3 expression was associated with poor prognosis in HGSOC patients (P < .05) and was found to promote proliferation and migration in HGSOC cell lines. GATA3 was released abundantly from TAM cells via exosomes and contributed to tumor growth in the tumor microenvironment. Moreover, GATA3 acted as a regulator for macrophage polarization and interactions between TAMs and HGSOC to support proliferation, motility, and cisplatin chemoresistance in mutant TP53 HGSOC cell lines. Furthermore, GATA3 played a critical role in the interactions between TAMs and mutant TP53 HGSOC to promote angiogenesis and epithelial-mesenchymal transition with epigenetic regulation. Targeting GATA3 using GATA3siRNA in TAMs impeded GATA3-driven proliferation, migration, cisplatin chemoresistance, and angiogenesis in mutant TP53 HGSOC cell lines. Our findings indicate that GATA3 plays a novel role in immunoediting of HGSOC and demonstrate that GATA3 may serve as a prognostic marker for HGSOC and a promising target in the treatment of HGSOC.
AB - High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic cancer. Emerging evidence suggests that tumor-associated macrophages (TAMs) play an immunosuppressive role in the tumor microenvironment and promote tumor growth, angiogenesis, and metastasis in ovarian cancer. Therefore, targeting TAMs in patients with ovarian cancer is an appealing strategy; however, all trials to date have failed. To improve the efficacy of this approach, we sought to elucidate the underlying mechanisms of the role of TAMs in ovarian cancer. We found that the developmental transcription factor GATA3 was highly expressed in HGSOC cell lines but not in the fallopian tube, which is the main origin of HGSOC. GATA3 expression was associated with poor prognosis in HGSOC patients (P < .05) and was found to promote proliferation and migration in HGSOC cell lines. GATA3 was released abundantly from TAM cells via exosomes and contributed to tumor growth in the tumor microenvironment. Moreover, GATA3 acted as a regulator for macrophage polarization and interactions between TAMs and HGSOC to support proliferation, motility, and cisplatin chemoresistance in mutant TP53 HGSOC cell lines. Furthermore, GATA3 played a critical role in the interactions between TAMs and mutant TP53 HGSOC to promote angiogenesis and epithelial-mesenchymal transition with epigenetic regulation. Targeting GATA3 using GATA3siRNA in TAMs impeded GATA3-driven proliferation, migration, cisplatin chemoresistance, and angiogenesis in mutant TP53 HGSOC cell lines. Our findings indicate that GATA3 plays a novel role in immunoediting of HGSOC and demonstrate that GATA3 may serve as a prognostic marker for HGSOC and a promising target in the treatment of HGSOC.
KW - GATA3
KW - High-grade serous ovarian carcinoma
KW - M2 macrophages
KW - Ovarian cancer
KW - TP53
KW - Tumor-associated macrophages
UR - http://www.scopus.com/inward/record.url?scp=85077921962&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077921962&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2020.109539
DO - 10.1016/j.cellsig.2020.109539
M3 - Article
C2 - 31935430
AN - SCOPUS:85077921962
SN - 0898-6568
VL - 68
JO - Cellular Signalling
JF - Cellular Signalling
M1 - 109539
ER -