Cross-Talk between Wnt and Hh Signaling Pathways in the Pathology of Basal Cell Carcinoma

Abstract

Basal cell carcinoma (BCC) is the most frequently occurring form of all cancers. The cost of care for BCC is one of the highest for all cancers in the Medicare population in the United States. Activation of Hedgehog (Hh) signaling pathway appears to be a key driver of BCC development. Studies involving mouse models have provided evidence that activation of the glioma-associated oncogene (GLI) family of transcription factors is a key step in the initiation of the tumorigenic program leading to BCC. Activation of the Wnt pathway is also observed in BCCs. In addition, the Wnt signaling pathway has been shown to be required in Hh pathway-driven development of BCC in a mouse model. Cross-talks between Wnt and Hh pathways have been observed at different levels, yet the mechanisms of these cross-talks are not fully understood. In this review, we examine the mechanism of cross-talk between Wnt and Hh signaling in BCC development and its potential relevance for treatment. Recent studies have identified insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), a direct target of the Wnt/β-catenin signaling, as the factor that binds to GLI1 mRNA and upregulates its levels and activities. This mode of regulation of GLI1 appears important in BCC tumorigenesis and could be explored in the treatment of BCCs.

The Therapeutic Relevance of Co-Targeting Wnt-Hh Signalling Pathways in Hepatocellular Carcinoma

“…Based on the relevant literatures regarding the functional interaction between Wnt and Hh pathways in various cancer models, the interaction between these two pathways could be either positive or negative [25]. In few cancer models Wnt is upstream of Hh [10] and in other cancers Hh is upstream of Wnt [26]. Additionally, in an in vitro study with gastrointestinal and lung cancer cells the activation of Wnt signalling pathway has been found to be associated with enhanced expression and activity of Hh signalling pathway [27].…”

“…Cells were plated in 6 well plates and cultured in DMEM (GIBCO, Invitrogen) media, supplemented with penicillin (100 U/ml), streptomycin (100U/ml) and 10% fetal bovine serum at 37°C in 5% CO 2-95% air atmosphere in a humidi- [12,13]. Development of resistance to a particular drug during the trial period is also an additional drawback as observed in case of Basal Cell Carcinoma [10]. Given the fact it is always necessary to investigate other potential druggable targets and better effective inhibitors of already known aberrant signalling pathways in HCC.…”

“…Keywords: Hepatocellular Carcinoma; Sulindac Sulphide; KAAD-Cyclopamine; Wnt/β-catenin; Hh/Gli1 resistance [7]. In various cancer models both pathways have been found to interact with each other at different levels and this interaction is known to play important role in the pathophysiology of those cancers like Pancreatic cancer [8], colon cancer [9] and in basal cell carcinoma [10]. Our previously published work demonstrated the role of Wnt and Hh pathway in progression of hepatocarcinogenesis in rodent model [6].…”

The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview

“…In the absence of functional PTCH, smoothened may be constitutively active, independent of hedgehog control, and may induce overexpression of several target genes including Wnts, CyclinD1 and D2, N-myc, Snail, the anti-apoptotic factor Bcl2 as well as feedback genes of Hh signaling (PATCH1 and 2, Gli1 and huntingtin interacting protein-1, Hip1) [70,71]. The Hh signaling pathway is in conjunction with other important pathways, such as epidermal growth factors (EGF/EGFR), transforming growth factor-β (TGF-β), and Wnt/β-catenin signaling [72,73]. Gli1 is also implicated in replicative immortality achieved by human telomerase reverse transcription transcriptase (hTERT) protein expression regulation [74].…”

Chronic exposure to cadmium induces a malignant transformation of benign prostate epithelial cells

“…Shh-associated secretory protein binds and inactivates patched1 (PTCH1), resulting in the release of smoothened protein and activation of GLI1, GLI2, and GLI3 receptors. GLI1 predominantly functions as a transcription activator, while GLI2 and GLI3 function as either an activator or repressor 21 . GLI1 activation initiates the expression of downstream target genes involved in proliferation (cyclin D1), survival (B-cell lymphoma-2, Bcl2), metastasis (Snail), and stem cell activation (Nanog and SOX2) 22 .…”