GLI2-Mediated Melanoma Invasion and Metastasis

Abstract

Melanoma represents approximately 4% of human skin cancers, yet accounts for approximately 80% of deaths from cutaneous neoplasms (1). Although progress has been made in understanding the genetics of the molecular events underlying melanoma oncogenesis (2-4), the clinical challenge remains enormous. A genetic hallmark of melanoma is the presence of activating mutations in the oncogenes BRAF and NRAS, which are present in 70% and 15% of melanomas, respectively, and lead to constitutive activation of mitogen-activated protein kinase pathway signaling (3,5). However, molecules that inhibit mitogen-activated protein kinase pathway-associated kinases, like BRAF and MEK, have shown only limited efficacy in the treatment of metastatic melanoma (6). Thus, a deeper understanding of the cross talk between signaling networks and the complexity of melanoma progression should lead to more effective therapy.Hedgehog (HH) signaling is controlled at the cell surface by two transmembrane proteins, the tumor suppressor Patched-1 (PTCH1), which acts as a HH receptor, and the oncoprotein Smoothened (SMO). In the absence of HH, PTCH1 maintains SMO in an inactive state. In the presence of any of the three HH ligands (Sonic, Indian, or Desert HH), inhibition of SMO by PTCH1 is alleviated and a signal is transduced that leads to the nuclear translocation and activation of GLI family transcription factors (7,8). GLIs are often overexpressed in cancers and contribute to the progression of a variety of neoplasms via regulation of cell cycle progression and apoptosis (9,10). One recent study (11) Article

Signaling Pathways Altered During the Metastatic Progression of Melanoma

“…Thus, metastatic and highly invasive tumors present TGF-β2 expression, while a minority of primary melanomas minimally invasive express TGF-β and in situ tumors does not express it [95]. In addition, melanoma secretes large amounts of TGF-β, and high amounts of TGF-β in plasma are associated with advanced tumor stages [96] since it foments tumor growth, angiogenesis, invasiveness and dissemination.…”

“…In a murine model of induced metastasis, cells with elevated expression of GLI2 caused bone metastasis, while cells with low level of this factor have reduced and heterogenic capacity to form metastasis. In addition, the GLI2 knockdown in an aggressive melanoma cell line (1205Lu) dramatically diminishes their ability to form bone metastasis [96].…”

Antagonistic functions of EMT-inducers in melanoma development: implications for cancer cell plasticity

“…Melanoma progression involves transition from a radial to a vertical growth phase, characterized by invasion into the dermis and subcutaneous tissue. Although the term "EMT" cannot be formally defined, differentiated melanocytes express Ecadherin and loss of this epithelial marker, a hallmark of EMT in carcinoma, is observed in late-stage melanoma that will invariably metastasize [12] .…”

Homing of Cancer Cells to the Bone

“…Recently, glioblastoma associated oncogene family zinc finger 2 (Gli2) a mediator of the sonic hedgehog pathway was identified as a transcriptional target for TGF-β in melanoma. Gli2 expression in melanoma cell lines associates with loss of E-cadherin expression, increased matrigel invasion and higher bone metastases [153]. BMPs are a family of growth factors that belong to the TGF-β superfamily.…”