Explore chapters and articles related to this topic
Molecular Mediator of Prostate Cancer Progression and Its Implication in Therapy
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Samikshan Dutta, Navatha Shree Sharma, Ridwan Islam, Kaustubh Datta
Mutations in spop (Speckle-type POZ protein) gene (6-15% of PCa) represents a subclass of fusion-negative PCa patients with poor prognosis [219–221]. SPOP is a POZ domain adaptor protein that modulates the transcriptional repression activities of genes and thus involve an error-prone method to repair broken DNA strands. SPOP forms a complex with CULLIN3 E3 ubiquitin ligase, and ubiquitinates for degradation of SRC-3/ AIB1, a cofactor of AR [222]. SPOP mutation therefore can activate AR in castration-resistant prostate cancer [223, 224]. SPOP mutation also activates Hedgehog pathway, polycomb group protein BMI1, which then promotes the progression of prostate cancer [225–227]. SPOP mutations are strongly associated with copy loss of CHD, FOXO3 and PRDM1 and rarely have accompanying mutations in PTEN or PIK3CA or TP53 in localized cancers [228]. SPINK1 overexpression is another molecular event found in 5-10% of PCa, which usually does not show gene rearrangement [229]. Although SPINK expression and ERG-negative status are not always mutually exclusive [230–232], SPINK1 encodes a secreted serine peptidase inhibitor, which may involve EGFR in its tumorigenic effects, and thus promotes an aggressive subtype of PCa [232]. It is strongly associated with copy loss of PTEN [230]. Other genetic events that are detected in fusion-negative prostate cancer are methylation of miR-26a, high expression of EZH2, and deletion of tumor suppressor MAP3K7/TAK1 [233–235].
Sorafenib-associated hand-foot skin reaction: practical advice on diagnosis, mechanism, prevention, and management
Published in Expert Review of Clinical Pharmacology, 2019
Leilei Ai, Ziheng Xu, Bo Yang, Qiaojun He, Peihua Luo
For researches of the mechanism of HFSR, there are following conjectures: (1) HFSR may cause toxic effects due to MTKI leakage after vascular injury. (2) Sorafenib inhibits c-kit receptor and causes the alteration of keratinocytes, thereby causing the incidence of HFSR. (3) Sorafenib inhibits PDGER and VEGFR pathways and the inhibition of VEGFR and PDGFR pathways may potentially prevent the vascular repair mechanism from functioning properly, thereby causing HFSR in high pressure areas such as the palms and soles of the feet. (4) Sorafenib can inhibit MAP3K7, leading to keratinocyte death.
Predictive biomarkers for the treatment of resectable esophageal and esophago-gastric junction adenocarcinoma: from hypothesis generation to clinical validation
Published in Expert Review of Molecular Diagnostics, 2018
Geny Piro, Carmine Carbone, Raffaela Santoro, Giampaolo Tortora, Davide Melisi
Baculoviral Inhibitor of Apoptosis (IAP) Repeat Containing (BIRC)3 codes for the cellular IAP (cIAP)2 protein [63], an IAP family member that blocks the caspase cascade inhibiting apoptosis [64,65]. A sequence analysis of BIRC3 promoter showed two NF-κB and two activator protein-1 (AP-1) responsive elements [66]. The TGF-β activated kinase (TAK)1 is a member of the serine/threonine kinase family, also known as mitogen-activated protein kinase kinase kinase 7 (MAP3K7), and is implicated in treatment resistance mechanisms, as well as TGF-β [67]. This protein is involved in several signaling pathways related to cell survival and inflammation and represents a crucial hub integrating the complex cell cytokine network and orchestrating the activation of AP-1 and NF-κB [68]. We proved that BIRC3 suppression, through genetic silencing or pharmacological inhibition of TAK1, dramatically reverted the intrinsic pancreatic cancer chemoresistance [69,70]. Basing on these finding, we assumed that BIRC3 expression modulated by TAK1 could also be responsible for distal esophageal and EGJ tumor resistance to chemoradiotherapy-induced cell death [71]. We demonstrated that the suppression of BIRC3 sensitized esophageal adenocarcinoma to apoptosis provoked by chemo and radiotherapy. In addition, we assessed BIRC3 mRNA expression in pretreatment bioptic specimens from 32 adenocarcinoma and 33 squamous cell carcinoma patients undergoing neoadjuvant chemoradiotherapy. We observed that BIRC3 tumor levels could not distinguish between the sensitive or resistant esophageal squamous cell carcinoma but significantly discriminated patients with sensitive or resistant adenocarcinoma, with Area Under the Curve (AUC) values of 0.7773 (95%CI = 0.604–0.95, P = 0.0075) or 0.8074 (95%CI = 0.634–0.98, P = 0.031), respectively, using the Size-based Pathological Response (SPR) or Tumor Regression Grade (TRG) classifications, respectively. Taken together, these results suggest that BIRC3 is a useful predictive marker to select patients with esophageal and EGJ adenocarcinoma who will most likely benefit from preoperative chemoradiotherapy.
Differential expression of MAP3K7 and TROPONIN C proteins and related perturbations in renal amyloidosis
Published in Expert Review of Proteomics, 2020
Nimisha Gupta, Tahreem Sahar, Dinesh Khullar, S.K. Jain, Saima Wajid
Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TGF-β activated kinase-1, is a serine/threonine kinase family protein. The TGF-β activates transcription factor, promotes mitogen-activated protein kinase (MAPK) signaling via the MAP3K7 and plays an important role in renal scarring leading to renal dysfunction [27]. MAP kinases are functionally connected kinases that control crucial cellular processes (transcription regulation and apoptosis), involving cell death, survival, differentiation and proliferation [28]. MAP3K family members phosphorylate thus activate JNK signaling which is a common feature in most of the human kidney injuries (both glomerular and tubular cells) as well as acute and chronic kidney injuries in the animal model. JNK signaling plays a crucial role in mechanisms of operating renal fibrosis [29]. Several studies demonstrated that MAP3K7/TAK1 activates the pro-inflammatory pathways, p38-MAPK and NF-κB that promote renal inflammation and fibrosis [30]. MAPK and JNK signaling pathways control proliferation, migration, extracellular matrix deposition, cell death and inflammation, thus they are essential determinants of chronic kidney diseases [27,29]. In addition to that, MAP3K7 along with its interactors were involved in various pathways like Wnt signaling, NF-κB signaling, TGF-β receptor signaling pathway and Alzheimer disease-amyloid secretase pathway (P) (Figure 5, Supplementary Table 4). Diverse reports have indicated that Wnt signaling is impaired in Alzheimer’s disease (AD) mouse models. Rojas et al. have been reported that loss of the Wnt signaling pathway may contribute to the pathogenesis of AD [31]. TGF-β receptor-mediated signaling has been proposed to mediate both the beneficial and deleterious roles for this cytokine in the Aβ function [32]. Recent evidence suggests that TGF-ligands interact directly with Aβ (1–40) thus, enhance the formation of amyloid-like aggregates. NF- κB regulates the expression of various cytokines (IL-1, IL-8 and TNF) and their critical linkage has been found with a variety of amyloid associated human diseases, such as Parkinson’s disease, Alzheimer’s disease and Rheumatoid Arthritis [33]. Alzheimer disease-amyloid secretase pathway (P) is actively involved in proteolytic processing of APP protein by β and γ secretase hence resulting in the generation of Alzheimer’s disease Aβ amyloid peptides [34]. These studies clearly establish the role of MAP3K7 in renal anomalies, thus justify our observation of increased expression of MAP3K7 in RA samples.