The Hedgehog-GLI pathway in embryonic development and cancer: implications for pulmonary oncology therapy

Abstract

Transcriptional regulation and epigenetic mechanisms closely control gene expression through diverse physiological and pathophysiological processes. These include the development of germ layers and post-natal epithelial cell-tissue differentiation, as well as, involved with the induction, promotion and/or progression of human malignancies.Diverse studies have shed light on the molecular similarities and differences involved in the stages of embryological epithelial development and dedifferentiation processes in malignant tumors of epithelial origin, of which many focus on lung carcinomas. In lung cancer, several transcriptional, epigenetic and genetic aberrations have been described to partly arise from environmental risk factors, but ethnic genetic predisposition factors may also play a role.The classification of the molecular hallmarks of cancer has been essential to study and achieve a comprehensive view of the interaction networks between cell signaling pathways and functional roles of the transcriptional and epigenetic regulatory mechanisms. This has in turn increased understanding on how these molecular networks are involved in embryo-layers and malignant diseases development. Ultimately, a major biomedicine goal is to achieve a thorough understanding of their roles as diagnostic, prognostic and treatment response indicators in lung oncological patients.Recently, several notable cell-signaling pathways have been studied based on their contribution to promoting and/or regulating the engagement of different cancer hallmarks, among them genome instability, exacerbated proliferative signaling, replicative immortality, tumor invasion-metastasis, inflammation, and immune-surveillance evasion mechanisms. Of these, the Hedgehog-GLI (Hh) cell-signaling pathway has been identified as a main molecular contribution into several of the abovementioned functional embryo-malignancy processes. Nonetheless, the systematic study of the regulatory epigenetic and transcriptional mechanisms has remained mostly unexplored, which could identify the interaction networks between specific biomarkers and/or new therapeutic targets in malignant tumor progression and resistance to lung oncologic therapy.In the present work, we aimed to revise the most important up-to-date experimental and clinical findings in biology, embryology and cancer research regarding the Hh pathway. We explore the potential control of the transcriptional-epigenetic programming versus reprogramming mechanisms associated with its Hh-GLI cell signaling pathway members. Last, we present a summary of this information to systematically integrate the Hh signaling pathway to identify and propose novel compound strategies or better oncological therapeutic schemes for lung cancer patients.

An Unbalanced Chromosome Translocation Between 7p22 and 12q13 Leads to ACTB-GLI1 Fusion in Pericytoma

“…The GLI1 protein is a transcription activator, GLI2 is both an activator and a repressor, GLI3 functions as a repressor, whereas there is no information on the function of GLI4 (16). The members of the GLI family are main mediators of the highly conserved Hedgehog signaling pathway, which plays a critical role in embryonic development (17)(18)(19)(20). Aberrant Hedgehog signaling is associated with the development and progression of various types of cancer and is implicated in multiple aspects of tumorigenesis (21)(22)(23)(24)(25)(26)(27).…”

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

“…The glioblastoma (GLI) zinc-finger transcription factors, acting as effectors of Sonic hedgehog (Shh) signaling, belong to the C2H2-type zinc finger protein subclass, which is critical for normal embryo development and cancer progression [134,135]. In dopaminergic neurons, MCPH7 functions through the Shh pathway by releasing the inhibition of tumor suppressor protein suppressor of fused (SUFU) to GLI1, and thereby enhances the Shh target gene transcription that is required for neural proliferation, protection, and regeneration [127].…”

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

“…In a simplified scenario, this bivalent chromatin, usually found in embryonic stem cells, maintains the developmental genes in a poised state for later activation or repression in a time and context-specific manner. Moreover, CSCs re-activate the so-called embryonic signaling pathways, including Wnt/β-catenin, Hedgehog and Notch, but also IL6/JAK/STAT3, NFκB, and PI3K/AKT, which in turn control the epigenetic dynamics in the cells in a positive feedback loop [49][50][51][52][53][54].…”