ΔNp63 mediates cellular survival and metastasis in canine osteosarcoma

Abstract

p63 is a structural homolog within the 53 family encoding two isoforms, ΔNp63 and TAp63. The oncogenic activity of ΔNp63 has been demonstrated in multiple cancers, however the underlying mechanisms that contribute to tumorigenesis are poorly characterized. Osteosarcoma (OSA) is the most common primary bone tumor in dogs, exhibiting clinical behavior and molecular biology essentially identical to its human counterpart. The purpose of this study was to evaluate the potential contribution of ΔNp63 to the biology of canine OSA. As demonstrated by qRT-PCR, nearly all canine OSA cell lines and tissues overexpressed ΔNp63 relative to normal control osteoblasts. Inhibition of ΔNp63 by RNAi selectively induced apoptosis in the OSA cell lines overexpressing ΔNp63. Knockdown of ΔNp63 upregulated expression of the proapoptotic Bcl-2 family members Puma and Noxa independent of p53. However the effects of ΔNp63 required transactivating isoforms of p73, suggesting that ΔNp63 promotes survival in OSA by repressing p73-dependent apoptosis. In addition, ΔNp63 modulated angiogenesis and invasion through its effects on VEGF-A and IL-8 expression, and STAT3 phosphorylation. Lastly, the capacity of canine OSA cell lines to form pulmonary metastasis was directly related to expression levels of ΔNp63 in a murine model of metastatic OSA. Together, these data demonstrate that ΔNp63 inhibits apoptosis and promotes metastasis, supporting continued evaluation of this oncogene as a therapeutic target in both human and canine OSA.

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

“…Interestingly, in contrast to our findings in this study, ΔNp63α was reported to be positively regulated by PI3K signaling in keratinocytes (63), and by the EGF receptor in squamous cell carcinoma cells (64). Notably, up-regulation of ΔNp63α has been implicated in promoting tumor metastasis in several settings (58)(59)(60). These inconsistencies may reflect differences between oncogenic and normal physiological signaling, depending on the cellular context.…”

“…Accumulating evidence indicates that decreased ΔNp63α expression may play a causative role in promoting cell motility and cancer metastasis (42,(58)(59)(60). In this study, we show that activation of three cancer signaling pathways, including PI3K, Ras, and Her2 signaling, promotes cancer cell motility and tumor metastasis by commonly targeting and repressing ΔNp63α expression.…”

Post-Transcriptional Control of Angiotensin II Type 1 Receptor Regulates Osteosarcoma Cell Death

“…The prognosis of OS is generally bad for the distal metastases [1-3]. In nowadays, the prognosis of patients with early OS could be improved with chemotherapy.…”

Understanding and Modeling Metastasis Biology to Improve Therapeutic Strategies for Combating Osteosarcoma Progression

“…To be successful in seeding distant sites, these metastatic precursors must acquire the ability to invade through the tissue matrix, intravasate into the circulation, arrest within the target tissue, extravasate, survive within each of these diverse and heterotypic environments, and then proliferate within the target organ in ways that recapitulate the primary solid tumor (111). Doing so requires the acquisition of myriad behaviors not typical of the cells of origin, and these transformed phenotypes can arise from abnormal activation of cell-autonomous pathways that endow tumor cells with, for example, resistance to apoptosis (112) or the ability to affect unusually high levels of capped mRNA translation (22). Beyond these shifts in behavior that represent intrinsic properties of the malignant cells themselves, disseminated tumor cells often acquire additional malignancy-associated behaviors from interactions with the normal tissues that surround them within the metastatic niche (113).…”