PTHrP promotes malignancy of human oral cancer cell downstream of the EGFR signaling.
Parathyroid hormone-related protein (PTHrP) is detected in many aggressive tumors and involved in malignant conversion; however, the underlying mechanism remains obscure. Here, we identified PTHrP as a mediator of epidermal growth factor receptor (EGFR) signaling to promote the malignancies of oral cancers. PTHrP mRNA was abundantly expressed in most of the quiescent oral cancer cells, and was significantly upregulated by EGF stimulation via ERK and p38 MAPK. PTHrP silencing by RNA interference, as well as EGFR inhibitor AG1478 treatment, significantly suppressed cell proliferation, migration, and invasiveness. Furthermore, combined treatment of AG1478 and PTHrP knockdown achieved synergistic inhibition of malignant phenotypes. Recombinant PTHrP substantially promoted cell motility, and rescued the inhibition by PTHrP knockdown, suggesting the paracrine/autocrine function of PTHrP. These data indicate that PTHrP contributes to the malignancy of oral cancers downstream of EGFR signaling, and may thus provide a therapeutic target for oral cancer.
Yamada
Tamaki
T
Laboratory of Pathophysiology and Signal Transduction, Department of Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan.
Tsuda
Masumi
M
Ohba
Yusuke
Y
Kawaguchi
Hideaki
H
Totsuka
Yasunori
Y
Shindoh
Masanobu
M
D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology*; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D044162:Parathyroid Hormone-Related Protein; D066246:ErbB Receptors