Parathyroid Hormone-Like Hormone is a Poor Prognosis Marker of Head and Neck Cancer and Promotes Cell Growth via RUNX2 Regulation

Abstract

Parathyroid Hormone-Like Hormone (PTHLH) is an autocrine/paracrine ligand that is up-regulated in head and neck squamous cell carcinoma (HNSCC). However, the cellular function and regulatory mechanism in HNSCC remains obscure. We investigated the clinical significance of PTHLH in HNSCC patients, and verified the role of RUNX2/PTHLH axis, which is stimulated HNSCC cell growth. In patients, PTHLH is a poor prognosis marker. PTHLH expression lead to increasing the cell proliferation potential through an autocrine/paracrine role and elevating blood calcium level in Nod-SCID mice. In public HNSCC microarray cohorts, PTHLH is found to be co-expressed with RUNX2. Physiologically, PTHLH is regulated by RUNX2 and also acting as key calcium regulator. However, elevations of calcium concentration also increased the RUNX2 expression. PTHLH, calcium, and RUNX2 form a positive feedback loop in HNSCC. Furthermore, ectopic RUNX2 expression also increased PTHLH expression and promoted proliferation potential through PTHLH expression. Using cDNA microarray analysis, we found PTHLH also stimulated expression of cell cycle regulators, namely CCNA2, CCNE2, and CDC25A in HNSCC cells, and these genes are also up-regulated in HNSCC patients. In summary, our results reveal that PTHLH expression is a poor prognosis marker in HNSCC patients, and RUNX2-PTHLH axis contributes to HNSCC tumor growth.

Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D spheroids

“…Besides its physiologic role as master regulator of osteogenic differentiation, several studies confirmed the tumor‐promoting role of RUNX2 in different cancer entities, including HNSCC (22, 36–39). Ectopic RUNX2 expression leads to an increased parathyroid hormone–like hormone expression and promotes proliferation of HNSCC cells (40). Moreover, RUNX2 was up‐regulated in HNSCC with lymph node metastasis and predicted poor prognosis in patients with HNSCC.…”

Interaction between Tumor-Associated Dendritic Cells and Colon Cancer Cells Contributes to Tumor Progression via CXCL1

“…Cancer cells are one source of PTHrP, which causes humoral hypercalcemia and promotes the osteolytic bone metastases of a malignancy by activating the type 1 PTH/PTHrP receptor (PTH1R) in the kidneys and skeleton [36]. PTHrP is also implicated in the regulation of the behavior of primary cancer by the paracrine/autocrine action model, including cell proliferation, migration, and invasion, and prevents cell death in different types of cancers [37,38,39]. PTHrP supports the metastatic potential of prostate cancer by protecting tumor cells from anoikis in both in vitro and in vivo models [40].…”

Underlying Ossification Phenotype in a Murine Model of Metastatic Synovial Sarcoma

“…PTHLH aids in regulating cell differentiation and proliferation, particularly in bone development, and promotes cell migration and invasion [16,17]. A significant prevention of apoptosis has also been observed with PTHLH upregulation [15]. RUNX2 (runt-related transcription factor 2), another gene involved in osteoblast differentiation, may stimulate PTHLH expression through IHH (Indian Hedgehog) [15], both of whose expressions are upregulated in our metastatic model when compared to the muscle model (Figure 4a).…”

“…The 47 genes identified in the mouse comparison were analyzed across the human tumors, and only one gene was found to be significantly different: parathyroid hormone-like hormone (PTHLH) (p-value = 0.0391, 95% CI = −2.56 to −0.068) (Figure 4c) (Supplemental Table S3). This gene is intriguing in that it is downstream of RUNX2, a master regulator of bone development and ossification, and a high expression has been correlated to a faster disease progression in a number of cancers (i.e., colon, prostate, breast, head, and neck) due to the overexpression of PTHLH [15][16][17][18]. Among its putative functions for cancer progression is the activation of myeloid-derived suppressor cells (MDSCs) in the bone marrow [18].…”