PMCID string | Title string | Sentences string |
|---|---|---|
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | For those reasons, and also due to its extracellular accessibility and ability to internalize, the TFRC has been used as a therapeutic target in cancers . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | To the best of our knowledge, TFRC protein expression has never been explored in human GIST tissues. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Our IHC results show that the TFRC was expressed in all human GIST tissues included in our cohort. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We demonstrate that a high level of TFRC is associated with high-risk GISTs, while a low level of TFRC is associated with very low risk, low-risk, and no-risk GIST samples. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | This is in line with what was observed in other types of cancers, such as breast, liver, and serous ovarian cancers, as well as esophageal squamous cell carcinoma . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | In addition, a positive association was found between a high level of TFRC and an elevated mitotic index, which is a major element in the assessment of the risk of relapse in GISTs . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Overall, we can speculate that a high level of TFRC is associated with poor prognosis in GISTs. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Moreover, our studies on GISTs reveal a positive correlation between TFRC expression and YAP expression and activation, which was not explored in other malignancies. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | This appears consistent with the literature since the TFRC is known to be a target of YAP . |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | In conclusion, our in vitro data establish a role of ferroptosis induction in GISTs. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Given the potential of targeting ferroptosis in various types of cancers , it is tempting to speculate that, also in GISTs, ferroptosis could be considered as a mechanism subjected to therapeutic targeting. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | We provide evidence that the pharmacological inhibition of YAP by VP induces ferroptosis in two human GIST cell lines, while CA3 induces ferroptosis independently of YAP inhibition. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Moreover, the study of TFRC expression in a human cohort of tissue samples from primary and metastatic GIST tumors reveals that the TFRC could be an attractive therapeutic target in high-risk GISTs and in GISTs with an elevated mitotic index. |
PMC9599726 | Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs) | Finally, our study on GIST TMA shows that a high TFRC expression was positively correlated with YAP nuclear localization, reflecting YAP activation. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Gastrointestinal stromal tumor (GIST) is the most common sarcoma located in gastrointestinal tract and derived from the interstitial cell of Cajal (ICC) lineage. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Both ICC and GIST cells highly rely on KIT signal pathway. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Clinically, about 80-90% of treatment-naive GIST patients harbor primary KIT mutations, and special KIT-targeted TKI, imatinib (IM) showing dramatic efficacy but resistance invariably occur, 90% of them was due to the second resistance mutations emerging within the KIT gene. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Although there are multiple variants of KIT mutant which did not show complete uniform biologic characteristics, most of them have high KIT expression level. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Notably, the high expression level of KIT gene is not correlated to its gene amplification. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Recently, accumulating evidences strongly indicated that the gene coding, epigenetic regulation, and pre- or post- protein translation of KIT mutants in GIST were quite different from that of wild type (WT) KIT. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | In this review, we elucidate the biologic mechanism of KIT variants and update the underlying mechanism of the expression of KIT gene, which are exclusively regulated in GIST, providing a promising yet evidence-based therapeutic landscape and possible target for the conquer of IM resistance. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Video Abstract Video AbstractImatinib resistance is the major obstacle for the cure of GIST, mostly due to second mutations within KIT gene for its reactivation. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Hence, drug development during the past decades was focused on kinase inhibitors, aiming to broader the spectrum of KIT kinase mutations effectively inhibited, including sunitinib, regorafenib and ripertinib, this benefit, however, is modest compared with imatinib. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | The reason is the emergence of secondary resistant mutations showing highly heterogeneous, and these TKIs are active against only a subset of the KIT secondary mutational spectrum, which constitutes the main determinant for treatment failure in imatinib-resistant GIST. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | However, one of the most important characteristics of GIST cells in both treatment-naive or TKIs-resistant cells is that its high dependency on KIT signal that necessitate the recapitulation of the underlying biology or mechanism of KIT mutations and expression, with the purpose of developing novel drugs, alone or combined with current KIT-TKIs, to prevent or reverse resistance via the complete elimination of KIT oncogenesis. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | The tyrosine kinase(TK) KIT was described for the first time in 1987 as the human cellular homologue of the feline sarcoma viral oncogene v-kit . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | It located on chromosome 4q12 and contains 976 amino acids, which encodes a transmembrane protein belonging to the type III family of RTK (receptor tyrosine kinases) . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | The extracellular segment contains five immunoglobulin-like structural domains (D1-D5), of them D1-D2-D3 are stem cell factor (SCF) binding regions, and D4-D5 are important units for KIT dimer formation . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | KIT is a transmembrane glycoprotein with ligand-induced TK activity . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Its ligand SCF was identified in 1990 and it exists both as a membrane-bound and soluble form . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Upon binding of SCF, dimerization of neighboring KIT receptors is mediated by homotypic interactions at the D4-D5 interface. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | This is followed by asymmetric arrangements of the cytoplasmic region of the KIT dimers associated to trans-autophosphorylation and final kinase activation . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Physiologically, in addition to interstitial cells of Cajal (ICC), KIT receptor is expressed in germ cells, bone marrow stem cells, melanocytes, and mast cells. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | In response to SCF stimulation, KIT propagates the signal of survival and proliferation to ICC, maintaining the function of gut motility [8–10]. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm located in the gastrointestinal tracts. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | The pathogenesis of GIST involve gain-of-function mutation in KIT (accounts for 75–80%), platelet-derived growth factor receptorα(PGFRA) (< 10%), or gene abnormalities including succinate dehydrogenase (SDH)-deficiency, the mutations of neurofibromin 1 (NF1), Kirsten rat sarcoma viral oncogene homolog (KRAS) and Harvey rat sarcoma viral oncogene homolog (HRAS) pro-oncogenes [11–13]. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | GIST cells arise from the musculature of ICC or their precursor cells and highly rely on the KIT expression for survival . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | KIT mutations is an early step for the development of GIST from ICC, meaning KIT necessitates the survival of GIST cells . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | KIT mutations, usually occur at the intracellular juxtamembrane (JM) WW domain (encoded by exon 11), or in the membrane-proximal extracellular domain (encoded by exons 8 or 9), accounting for approximately 85–90% of KIT-mutant GIST, they endows KIT gene an oncogenic capacity to proliferate and form tumors via the intermediates of PI3K-AKT, JAK-STAT and RAS-RAF-MEK-ERK (MAPK) cascades [9, 12, 17–19]. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | With the discovery of this druggable KIT mutations, KIT-targeted inhibition with first line Imatinib (IM) become standard of care and offers meaningful clinical benefit in metastatic GIST patients . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | However, the primary KIT variants showing different sensitivity to IM, treatment resistance is common and occurs between 18–24 months of imatinib treatment due to resistant clones, warranting a switch to second and beyond-second lines of tyrosine kinase inhibitors (TKIs) including sunitinib, regorafenib and repritinib as per the guideline, but only with modest efficacy [21–23]. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Furthermore, almost all of the patients will progress presented with the metastasis to multiple organs and each of these metastases, or even in the same primary lesion can have different genomic mutations with KIT . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | These range from point mutations or insertions to large indel variants, which exhibit variable biological traits, including intracellular mis-location, and downstream target molecules, which possibly as the determinants to the response to IM . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Moreover, the sole transcription factors were identified in the regulation of these KIT mutants, showing much more different from that of wild type (WT) KIT . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | These distinct regulation of KIT in GIST could also be causative for its blocked degradation. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | In fact, KIT expression was observed in 95% of GIST, as a diagnostic algorithm using upfront immunohistochemistry (IHC) markers of KIT (CD117) positivity in GIST , and with IM treatment, KIT transcript or/ and protein derived from multiple heterogeneous KIT mutations in IM-resistant cells is higher than that in pre-IM counterparts [31–33], implying the compensatory up-regulation of KIT possibly contributing to secondary resistance to IM. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Here, we summarize various of KIT variants and its core regulated network, focus on the process of gene regulation, transcription and protein translation, with emphasis on the therapeutical vulnerability and clinical strategy for targeting oncogenic KIT kinase dependency in GIST. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Within the larger group of KIT-mutated GIST, different mutations’ hotspots have been reported, of which the vast majority of KIT mutations are found in exon 11 coding for JM (66–71%), exon 9 coding for extracellular domain (13%), exon 13 coding TK domain I (ATP binding pocket) (1–3%), and exon 17 coding for TK domain II (activation loop) (1–3%). |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | The ATP-binding pocket, encoded by exon 13 and 14, whose mutations directly interfere with IM binding, or the activation ring, where mutations can stabilize the KIT's active conformation . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | The gain-of-function of KIT mutations resulting in the constitutive activation of the protein, genomic context and alternative signaling pathways, also largely affect the efficacy of IM, as well as sunitinib, and regrifinib and ripritinib, which mostly due to the different transcriptional programs observed in GIST with various genotypes that influenced the protein active structures, dimerization affinity, and cellular localization . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Indeed, clinically, most GIST show strong, diffuse cytoplasmic staining, whereas nearly half show concurrent dot-like (bGolgiQ pattern) staining and occasionally, only dot-like or even membranous staining is seen . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | In vitro GIST cell lines, different KIT mutations were detected, such as classical GIST-T1 (primary mutation in KIT exon 11—Δ560–578) and GIST-882 (primary mutation in KIT exon 13—K642E) cell models, the biological effects upon imatinib treatment can be significantly different [38–40]. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Notably, as shown in Table 1, the involved down-streams varied across different KIT genotypes, and which also be compelling factors impact tumor behavior and IM sensitivity. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Table 1KIT mutation and its activated downstream in GIST cell linesCell linesKIT mutationsMutation downstreamTKI resistance and IC50 (nM)IM SU RERefGIST-T1Exon 11: V570-Y578 (Hom)MAPK pathwayPI3K pathwayWnt pathwayNotch pathwaySTAT3S S S16.54 15.00 110.00[41–46]GIST-882Exon 13: K642E (Hom)MAPK pathwayPI3K pathwaySTAT3R S R173.00 54.00 503.00GIST-48Exon 11: V560D (Hom)Exon 17: D820A (Het)MAPK pathwayPI3K pathwayJAK/STAT pathwayR R R413.00 587.00 164.00GIST-430Exon 11: (V560-L576) (Het)Exon 13: V654A (Het)MAPK pathwayPI3K pathwayR R R61.00 68.00 191.00[44, 49–51]GIST-BOEExon 9: A502_Y503dupMAPK pathwayR NR NRNRGIST-PSWExon 11: K558_G565delinsRMAPK pathwayS NR NRNRHG129Exon 11: 45 bp insertion between F591- 592GMAPK pathwayS NR NR42.00 NR NRGIST-522Exon 11: delEVQWK554-558 (het)NRR NR NRNRGIST-62Exon 11: MYEVQWK552-558T (het)NRR NR NRNRGIST-226Exon 11: P551-W557 (Hom)Exon 17: Y823D (Hom)MAPK pathwayR R R > 5000.00 3856.00 > 5000.00GIST-48BExon 11: V560D (Hom)Exon 17: D820A (Het)MAPK pathwayR R R > 5000.00 > 5000.00 > 5000.00GIST-5Exon 11NRNRNRGIST-474Exon 11NRNRNRHG209Exon 11: delYIDPTQL 570–576Exon 17: D816HMAPK pathwayR R NR > 1000.00 NR NRGIST-544Exon9: AY503-504ins (Het)MAPK pathwaySTAT1 and STAT3NRNRIM Imatinib, SU Sunitinib, RE Regorafenib, Hom Homozygous, Het Heterozygous, + KIT positive,—KIT negative, S Sensitive, R Resistance, NR Not reported KIT mutation and its activated downstream in GIST cell lines MAPK pathway PI3K pathway Wnt pathway Notch pathway STAT3 S S S 16.54 15.00 110.00 MAPK pathway PI3K pathway STAT3 R S R 173.00 54.00 503.00 Exon 11: V560D (Hom) Exon 17: D820A (Het) MAPK pathway PI3K pathway JAK/STAT pathway R R R 413.00 587.00 164.00 Exon 11: (V560-L576) (Het) Exon 13: V654A (Het) MAPK pathway PI3K pathway R R R 61.00 68.00 191.00 R NR NR NR S NR NR NR S NR NR 42.00 NR NR R NR NR NR R NR NR NR Exon 11: P551-W557 (Hom) Exon 17: Y823D (Hom) R R R > 5000.00 3856.00 > 5000.00 Exon 11: V560D (Hom) Exon 17: D820A (Het) R R R > 5000.00 > 5000.00 > 5000.00 NR NR NR NR Exon 11: delYIDPTQL 570–576 Exon 17: D816H R R NR > 1000.00 NR NR MAPK pathway STAT1 and STAT3 NR NR IM Imatinib, SU Sunitinib, RE Regorafenib, Hom Homozygous, Het Heterozygous, + KIT positive,—KIT negative, S Sensitive, R Resistance, NR Not reported Generally, DNA expression is regulated by the cis-regulatory elements (CREs), which consists of enhancers and super-enhancers transcription factors which comprise of transcription factors and the recruited co-activators and RNA Polymerase II (RNA Pol II). |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Over-expression of KIT in GIST results from the dysregulation of a large enhancer domain in the DNA strand, but rarely related to its DNA amplification . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | CHIP-seq of GIST tumor samples and cell lines identified the enhancer domain to be driving KIT gene expression, which is unique and essential for KIT gene expression and cell viability in GIST. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Accordingly, exclusive transcription factors model the expression of GIST-type mutant KIT gene which facilitates tumorgenesis and progression . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Moreover, GIST cells are highly dependent on KIT expression, which was due to epigenetic regulation rather than amplification in KIT oncogene . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | However, as more epigenetic mechanisms elucidated in mesenchymal tumors, reversible epigenetic changes can be identified and appears to be an important novel approach to understand the formation, prognosis and therapeutic strategies of various types of mesenchymal tumors [63–65]. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Figure 1 shows KIT mutations and expression in GIST and its role in epigenetics and multifaceted biological modifications. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Fig. 1Gene and epigenetic regulations of KIT expression in GIST. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | KIT extracellular segment contains five immunoglobulin-like structural domains (D1-D5), D1-D2-D3 are stem cell factor (SCF) binding regions, and D4-D5 are important units for KIT dimer formation. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | In the absence of ligand stimulation, two adjacent KIT protein D4 structures remain independent due to charge repulsion. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | KIT mutations usually arise in the extracellular domains (exon 9), the juxtamembrane domain (exon 11) and in the kinase I and II domains (exons 13 and 17). |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | The SCF binding to KIT and then changes the conformation of KIT and promote its dimerization, thereby activating tyrosine kinase activity in the intracellular segment by recruiting and phosphorylating substrates, thus forming signal transduction. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | But once KIT mutated, it disrupts its self-inhibition mechanism, resulting in continuous activation of signaling pathways such as Ras-Erk within the cell. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | FOXF1, ETV1 and HIC1 together form the core TF network in GIST binding enhancer and/or promoter and then promoting KIT expression. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | BRD4 (function as “readers”), HAND1 and BRAX1 positive regulate the core TF network. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Transcription factor MITF and BIRC5 promote KIT transcription. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | MiRNA-20a, miRNA-17–92, miRNA200b-3p, miRNA-494, miRNA-148-3p are tumor suppressors downregulate KIT transcription and the majority of them directly bind to the 3’-UTR domain of relevant mRNA; the first three mentioned miRNAs can inhibit ETV1 mRNA levels, miRNA-494 can inhibit BIRC5 expression suggesting a negative feedback mechanism. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | SH3BP2 promotes the expression of mutant KIT by up-regulation of the expression of MITF and ETV1. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | FTO, functions as a “eraser”, promoting m6A demethylation increases the expression of KIT. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Normal KIT chromosomal has CTCF insulator creating a topological boundary. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Once CTCF insulator displaced by DNA methylation, allowing the super-enhancer to contact and induce KIT Gene and epigenetic regulations of KIT expression in GIST. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | KIT extracellular segment contains five immunoglobulin-like structural domains (D1-D5), D1-D2-D3 are stem cell factor (SCF) binding regions, and D4-D5 are important units for KIT dimer formation. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | In the absence of ligand stimulation, two adjacent KIT protein D4 structures remain independent due to charge repulsion. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | KIT mutations usually arise in the extracellular domains (exon 9), the juxtamembrane domain (exon 11) and in the kinase I and II domains (exons 13 and 17). |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | The SCF binding to KIT and then changes the conformation of KIT and promote its dimerization, thereby activating tyrosine kinase activity in the intracellular segment by recruiting and phosphorylating substrates, thus forming signal transduction. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | But once KIT mutated, it disrupts its self-inhibition mechanism, resulting in continuous activation of signaling pathways such as Ras-Erk within the cell. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | FOXF1, ETV1 and HIC1 together form the core TF network in GIST binding enhancer and/or promoter and then promoting KIT expression. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | BRD4 (function as “readers”), HAND1 and BRAX1 positive regulate the core TF network. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Transcription factor MITF and BIRC5 promote KIT transcription. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | MiRNA-20a, miRNA-17–92, miRNA200b-3p, miRNA-494, miRNA-148-3p are tumor suppressors downregulate KIT transcription and the majority of them directly bind to the 3’-UTR domain of relevant mRNA; the first three mentioned miRNAs can inhibit ETV1 mRNA levels, miRNA-494 can inhibit BIRC5 expression suggesting a negative feedback mechanism. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | SH3BP2 promotes the expression of mutant KIT by up-regulation of the expression of MITF and ETV1. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | FTO, functions as a “eraser”, promoting m6A demethylation increases the expression of KIT. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Normal KIT chromosomal has CTCF insulator creating a topological boundary. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Once CTCF insulator displaced by DNA methylation, allowing the super-enhancer to contact and induce KIT The regulations of gene are mainly connected with transcription factor (TF), which directly interpret the genome, and no exception in the change of KIT gene . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | It seems that TFs forming the regulatory network exclusively act on the enhancers of KIT gene in GIST, showing its rudiment [62, 68–70]. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | In addition, the study of how TF linked to essential chromatin regulators will also provide important insights into the gene regulation and epigenetic mechanisms of GIST . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Forkhead box F1 (FOXF1) is a member of the forkhead box (FOX) family, which contains a highly conserved DNA binding region (DBD) . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | As one of the key TFs, FOXF1 is required for the lineage differentiation of ICCs, as well as the growth of GIST cells. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | FOXF1 functions as a pioneer factor that modulates the chromatin accessibility for ETS translocation variant 1 (ETV1), after which they accumulate in the enhancer domain of the mutant KIT gene, promoting KIT expression . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | ETV1, an ETS family transcription factor, is located on chromosome 7p21 . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | It is involved in the tumorigenesis of multiple cancer types, including prostate cancer and melanoma, where it regulates distinct transcriptional programs . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | ETV1 is also a master regulator of the ICC lineage, and it is essential for the development of the subtypes of ICCs which are sensitive to oncogenic KIT-mediated transformation. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Moreover, ETV1 directly binds to the enhancer and promoter regions of KIT gene and thus forming a positive feedback regulation that advances their expression . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Notably, the protein of ETV1 is highly unstable, and active mitogen-activated protein kinase (MAPK) can increase its stability. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | KIT mutants activate the downstream, MAPK, leading to the stabilization of the ETV1 protein and oncogenic ETS transcript program. |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | Co-activators cyclic AMP-responsive element-binding protein (CREB)-binding protein (CBP) and p300 interact with an oncoprotein ETS translocation variant 1(ETV1), which directly acetylates ETV1, thus enhancing its stability, DNA-binding capacity, and transcriptional activity in vitro . |
PMC10898159 | KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST | This mechanism of ETV1 in GIST differs from that in the other ETS-dependent tumors, such as genomic translocation or amplification in prostate cancer . |
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