Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer
Pradeep Chaluvally-Raghavan,
Kang Jin Jeong,
Sunila Pradeep,
Andreia Machado Silva,
Shuangxing Yu,
Wenbin Liu,
Tyler Moss,
Cristian Rodriguez-Aguayo,
Dong Zhang,
Prahlad Ram,
Jinsong Liu,
Yiling Lu,
Gabriel Lopez-Berestein,
George A. Calin,
Anil K. Sood,
Gordon B. Mills
Affiliations
Pradeep Chaluvally-Raghavan
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Corresponding author
Kang Jin Jeong
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Sunila Pradeep
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Andreia Machado Silva
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Shuangxing Yu
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Wenbin Liu
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Tyler Moss
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Cristian Rodriguez-Aguayo
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Dong Zhang
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Prahlad Ram
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Jinsong Liu
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Yiling Lu
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Gabriel Lopez-Berestein
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
George A. Calin
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Anil K. Sood
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Gordon B. Mills
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Corresponding author
Summary: 3q26.2 amplification in high-grade serous ovarian cancer leads to increased expression of mature microRNA miR551b-3p, which is associated with poor clinical outcome. Importantly, miR551b-3p contributes to resistance to apoptosis and increased survival and proliferation of cancer cells in vitro and in vivo. miR551b-3p upregulates STAT3 protein levels, and STAT3 is required for the effects of miR551b-3p on cell proliferation. Rather than decreasing levels of target mRNA as expected, we demonstrate that miR551b-3p binds a complementary sequence on the STAT3 promoter, recruiting RNA polymerase II and the TWIST1 transcription factor to activate STAT3 transcription, and thus directly upregulates STAT3 expression. Furthermore, anti-miR551b reduced STAT3 expression in ovarian cancer cells in vitro and in vivo and reduced ovarian cancer growth in vivo. Together, our data demonstrate a role for miR551b-3p in transcriptional activation. Thus, miR551b-3p represents a promising candidate biomarker and therapeutic target in ovarian cancer. : Chaluvally-Raghavan et al. find that miR551b-3p affects transcription of STAT3. The authors find that miR551b-3p binds to the STAT3 promoter and facilitates RNA polymerase II and TWIST1 transcription factor recruitment, which in turn activates STAT3 transcription.