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  • MAPK are involved in a large variety of

    2022-06-29

    MAPK are involved in a large variety of solid and hematolgical neoplasms and, indeed, several components of the MAPK network have already been proposed as targets in cancer therapy, such as p38, JNK, ERK1/2, MEK1/2, RAF, RAS, DUSP1 and ERK5 [11], [12]. Among them, alteration of the RAS-RAF-MEK1/2-ERK1/2 pathway has frequently been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations in genes of the pathway itself [13]. Components of JNK and p38 pathways are rarely mutated in cancer compared to those of the ERK1/2 pathway. Nevertheless, alterations in JNK and p38 signaling are associated to cancer, although they may act either as oncogenes or tumor suppressors depending on the cellular context [14]. ERK5 is also involved in human cancers including those of the prostate, breast and liver [15], [16].
    The canonical Hedgehog signaling pathway Initially discovered in Drosophila, the Hedgehog (HH) signaling is an evolutionarily conserved pathway that plays a crucial role in patterning, proliferation and differentiation during embryogenesis [17], [18]. In the adult it is mostly active in stem/progenitor cells, where it regulates tissue homeostasis, repair and regeneration [19]. Canonical HH pathway activation is initiated by the binding of HH ligands, Sonic (SHH), Indian (IHH) and Desert Hedgehog (DHH), to the 12-pass transmembrane protein receptor patched (PTCH), which reside in the primary cilium [20], [21], [22]. Upon HH binding, PTCH relieves its inhibition on the G-protein-coupled receptor-like smoothened (SMO), which translocates into the tip of the cilium and triggers a cascade of events that promote the formation of activator forms of the GLI transcription factors (GLI-A). GLI2 and GLI3 translocate into the nucleus and induce transcription of HH pathway target genes, including GLI1 [23], [24], [25]. In absence of HH ligands, PTCH inhibits pathway activation by preventing SMO to enter the cilium. This results in phosphorylation and proteasome-mediated carboxyl cleavage of GLI2 and GLI3 to their repressor forms (GLI2/3-R) [26], [27]. GLI1 is degraded by the proteasome and transcriptionally repressed, with consequent inhibition of the pathway. GLI1 acts as an activator, whereas GLI2 and GLI3 display both positive and negative transcriptional functions [26], [28], [29]. The GLI transcription factors activate the GSK126 of a number of targets, including regulators of proliferation and differentiation (e.g. CyclinD1 and D2, N-Myc, E2F1, PDGFRα, Igf2, FoxM1, FoxF1, Hes1, Igfbp3, Neogenin), survival (Bcl2), angiogenesis (Vegf, Cyr61), self-renewal (Bmi1, Nanog, Sox2), epithelial-mesenchymal transition (Snail1, Sip1, Elk1) and invasiveness (Osteopontin). The HH pathway target genes include GLI1, which further amplifies the initial HH signaling, and the HH pathway negative regulators PTCH1 and HHIP1, which restrain the HH signaling. Abnormal activation of the HH-GLI pathway is implicated in a variety of tumors, including those of the skin, brain, lungs, prostate, breast, gastrointestinal tract and blood. Multiple mechanisms of HH pathway activation have been described in cancer [30]. Ligand-independent activation is caused by loss-of-function mutations in the negative regulators PTCH1 [31], [32], SUFU [33], [34] or REN [35], activating mutations in SMO [36], or gene amplifications of GLI1 and GLI2 [37], [38], that results in constitutive HH pathway activation. This type of HH pathway activation occurs more often in basal cell carcinoma (BCC), medulloblastoma and rhabdomyosarcoma. Ligand-dependent autocrine activation of the HH pathway has been identified in several types of cancer, including lung, pancreas, gastrointestinal tract, prostate and colon cancer, glioma and melanoma [39], [40], [41], [42], [43], [44], [45], [46], [47], [48]. In this case, tumor cells secrete and respond to HH ligands and show increased HH ligands expression apparently in absence of genetic aberrations of HH pathway components. In the ligand-dependent paracrine activation of HH pathway, a mode of action that resembles the physiological HH signaling during development, HH ligands secreted by cancer cells activate HH signaling in the surrounding stroma rather than in the tumor itself. The mechanisms by which the HH signaling and the tumor stroma interact during paracrine signaling are not completely understood. Evidence supporting this mechanism has revealed from studies in human tumor xenograft models of pancreatic and colorectal cancers [49]. Similarly, the reverse paracrine HH pathway activation, in which HH ligands are secreted by the tumor microenvironment and activate the pathway in tumor cells, has been described in an experimental model of glioma [50] and in hematological malignancies, such as B-cell lymphoma and mantle cell lymphoma [51], [52].