Hedgehog and TGFβ signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma
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Shellese A. Cannonier1,2,3, Cara B. Gonzales4, Kim Ely5, Scott A. Guelcher2,6,7, Julie A. Sterling1,2,3,7,8
1Department of Veteran Affairs, Tennessee Valley Healthcare System, Nashville TN 37212, USA
2Center for Bone Biology, Vanderbilt University Medical Center, Nashville TN 37232, USA
3Department of Cancer Biology, Vanderbilt University Medical Center, Nashville TN 37232, USA
4Department of Comprehensive Dentistry, University of Texas Health Science Center San Antonio Dental School, San Antonio, TX 78229, USA
5Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville TN 37232, USA
6Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville TN 37235, USA
7Department of Biomedical Engineering, Vanderbilt University, Nashville TN 37235, USA
8Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville TN 37232, USA
Julie A. Sterling, email: [email protected]
Keywords: oral cancer, Gli2, hedgehog, TGF-B, parathroid hormone related protein (PTHrP)
Received: February 11, 2016 Accepted: September 27, 2016 Published: October 12, 2016
Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide. OSCC invasion into the lymph nodes and mandible correlates with increased rates of recurrence and lower overall survival. Tumors that infiltrate mandibular bone proliferate rapidly and induce bone destruction. While survival rates have increased 12% over the last 20 years, this improvement is attributed to general advances in prevention, earlier detection, and updated treatments. Additionally, despite decades of research, the molecular mechanisms of OSCC invasion into the mandible are not well understood. Parathyroid Hormone-related Protein (PTHrP), has been shown to be essential for mandibular invasion in OSCC animal models, and our previous studies demonstrate that the transcription factor Gli2 increases PTHrP expression in tumor metastasis to bone. In OSCC, we investigated regulators of Gli2, including Hedgehog, TGFβ, and Wnt signaling to elucidate how PTHrP expression is controlled. Here we show that canonical Hedgehog and TGFβ signaling cooperate to increase PTHrP expression and mandibular invasion in a Gli2-dependent manner. Additionally, in an orthotopic model of mandibular invasion, inhibition of Gli2 using shRNA resulted in a significant decrease of both PTHrP expression and bony invasion. Collectively, our findings demonstrate that multiple signaling pathways converge on Gli2 to mediate PTHrP expression and bony invasion, highlighting Gli2 as a therapeutic target to prevent bony invasion in OSCC.
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