Abstract
The hedgehog (SHH) signaling pathway is primarily involved in embryonic gut development, smooth muscle differentiation, cell proliferation, adult tissue homeostasis, tissue repair following injury, and tissue polarity during the development of vertebrate and invertebrate organisms. GLIoma-associated oncogene homolog (GLI) family of zinc-finger transcription factors and smoothened (SMO) are the signal transducers of the SHH pathway. Both SHH ligand-dependent and independent mechanisms activate GLI proteins. Various transcriptional mechanisms, posttranslational modifications (phosphorylation, ubiquitination, proteolytic processing, SUMOylation, and acetylation), and nuclear-cytoplasmic shuttling control the activity of SHH signaling pathway proteins. The dysregulated SHH pathway is associated with bone and soft tissue sarcomas, GLIomas, medulloblastomas, leukemias, and tumors of breast, lung, skin, prostate, brain, gastric, and pancreas. While extensively studied in development and sarcomas, GLI family proteins play an essential role in many host-pathogen interactions, including bacterial and viral infections and their associated cancers. Viruses hijack host GLI family transcription factors and their downstream signaling cascades to enhance the viral gene transcription required for replication and pathogenesis. In this review, we discuss a distinct role(s) of GLI proteins in the process of tumorigenesis and host-pathogen interactions in the context of viral infection-associated malignancies and cancers due to other causes. Here, we emphasize the potential of the Hedgehog (HH) pathway targeting as a potential anti-cancer therapeutic approach, which in the future could also be tested in infection-associated fatalities.
Highlights
Hedgehog (HH) signaling is a necessary, evolutionarily conserved developmental process for human embryogenesis and organogenesis
The HH pathway plays an essential role in cell proliferation, differentiation, apoptosis, and migration, and it cross-talks with signaling pathways such as mitogen-activated protein kinase (MAPK)/ERK, PI3K/AKT/mTOR, EGFR, and NOTCH (Figure 3) [52,58,59,60]. tGLI1 has been reported as a stronger promoter of tumor migration and invasion as compared to GLI1 in glioblastoma and breast cancer [61]
The same study stated that high levels of Sonic HH (SHH), Patched 1 (PTCH1), and GLI2 are focally expressed in the epithelium of carcinoma in situ, suggesting potential early screening possibilities for unusual HH signaling activity [99]
Summary
Hedgehog (HH) signaling is a necessary, evolutionarily conserved developmental process for human embryogenesis and organogenesis. First identified in Drosophila melanogaster, HH signaling is extensively used to explain the complex topic of cell segment number patterning. SHH signaling promotes adult stem cells’ proliferation, including primitive hematopoietic [2], mammary, and neural stem cells [3]. Can alter their fates in adult tissues and cause aberrant upregulation of the HH signaling pathway. Oncogenic mechanisms include cell proliferative capacity, angiogenesis, epithelial to mesenchymal transition (EMT), and invasive migration patterns typical of metastatic tissues [4,5,6]. Downstream HH signaling protein families such as GLI have become the spotlight as targets for invasive epithelial cancers. We discuss the prospect of HH/GLI signaling in cancers due to viral infections and other causes
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