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Familial Gastrointestinal Stromal Tumor Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Individuals with NF1 mutations are at high risk of developing GIST. Similar to germline KIT mutations, NF1-related GIST begins with preneoplastic ICCH (diffuse and focal hyperplastic foci of CD117-positive ICC, often found around nerve plexuses) followed by LOH in chromosomes 14q and 22q. Interestingly, these frequently deleted regions encompass a number of functionally important genes, including PARP2 (regulating DNA repair and apoptosis and thus suppressing genomic instability), APEX1 (encoding a DNA repair enzyme implicated in the base excision pathway), and NDRG2 (inhibiting tumor proliferation and promotes apoptosis) at chromosome 14q11.2; SIVA (encoding a pro-apoptotic protein that binds to the tumor necrosis factor receptor CD27) at chromosome 14q32.33; MAX (encoding a basic helix-loop-helix leucine zipper transcription factor that interacts with MYC, its heterozygous or homozygous inactivating mutations accounting for 17% of sporadic GIST and 50% of sporadic and NF-1-associated GIST) at chromosome 14q23.3; and NF2 (encoding merlin that inhibits the activities of RAS and RAC, and suppresses tumor cell growth) at chromosome 22q12.2.
Adrenal Tumors
Published in Dongyou Liu, Tumors and Cancers, 2017
Molecularly, ACC is linked to chromosomal gains and losses; hypermethylation of the promoters of specific genes (e.g., H19, PLAGL1, G0S2, and NDRG2); TP53-inactivating mutations (LFS); insulin-like growth factor (IGF2) overexpression (BWS); mutations in MENIN (MEN1), APC (FAP), NF1 (NF1), and PRKAR1A (Carney complex) genes; and constitutive activation of the Wnt/β-catenin signaling pathway via activating mutations of the beta-catenin gene (CTNNB1) [3,4].
FXR modulators for enterohepatic and metabolic diseases
Published in Expert Opinion on Therapeutic Patents, 2018
Hong Wang, Qingxian He, Guangji Wang, Xiaowei Xu, Haiping Hao
HCC is the most common type of primary liver cancer in adults, which occurs in the setting of chronic liver inflammation or fibrosis. A large body of evidence indicates that FXR is a cell protector in the liver, participating in liver regeneration, hepatic fibrosis, and liver inflammation. The potential function of FXR in liver cancer has been witnessed from the fact that Fxr−/− mice were found to spontaneously develop liver tumors as they aged [41], and the expression of FXR are downregulated in human hepatocellular carcinoma specimens [118]. In the diethylnitrosoamine (DEN)-mediated liver cancer mouse model, GW4064 is found to reduce the expression of gankyrin, which participates in the repressing of tumor suppressor proteins [119]. N-myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor, which participates in the development and metastasis of human liver cancer. In livers of Fxr−/− mice and human HCC patients, NDRG2 mRNA is diminished. While stable overexpression of FXR or Px-102 treatment leads to the transcriptional induction of the NDRG2 gene and reduced liver tumor growth in an orthotopic xenograft model in nude mice [120]. Besides, INT-767 administration to Abcb4−/− mice, which characterized as accumulation of BA and development of HCC, significantly reduced the number and size of HCC [121]. Conclusively, these clues suggest that FXR agonists may be applicable to the prevention and therapy of HCC, and of course this requires much more pre-clinical and clinical validation.
The role of the Fas/FasL signaling pathway in environmental toxicant-induced testicular cell apoptosis: An update
Published in Systems Biology in Reproductive Medicine, 2018
The transcriptional regulation of FasL is a complex process involving a variety of transcription factors, mainly dependent on the nuclear factor of activated T cells (NFAT) in T lymphocytes. Chai et al. (2008) demonstrated that activated NFAT is transported from the cytoplasm to the nucleus, which then specifically binds to the NFAT target gene located in the −201 to +71 region of the FasL promoter sequence; NFAT directly promotes FasL transcription in stromal tumor cells, which results in Leydig cell apoptosis (Chai et al. 2008). NF-kB and Fas, both pro-apoptotic factors, are closely linked to Leydig cell apoptosis. NDRG2, which is located in the cytoplasm of Leydig cells, is involved in cell differentiation, development, and apoptosis. After Leydig cells are exposed to toxicants, activated Fas sequesters NF-kB from IkB via RIP and pro-caspase-8. NF-kB, migrates into the nucleus and binds to the NDRG2 promoter. NDRG2 is upregulated when it is stimulated by apoptosis and migrates back to the nucleus. In conjunction, NF-kB receives feedback from the signal to regulate downstream genes (Li et al. 2012). N-acetylcysteine (NAC) appears to effectively antagonize the activation of the Fas/FasL signaling pathway in Leydig cell apoptosis (Aggarwal et al. 2012) (Figure 4).
Overexpression of NDRG2 promotes the therapeutic effect of pazopanib on ovarian cancer
Published in Journal of Receptors and Signal Transduction, 2021
Ying Cui, Guihua Shen, Linlin Ma, Qiubo Lv
Ovarian cancer causes more than 239,000 cases and 152,000 death around the world each year [1], remains to be the leading cause of cancer-related death in most developed countries. Epithelial ovarian were classified into several categories including serous carcinomas (SC), mucinous carcinomas (MC), endometrioid carcinomas (EC), and clear-cell carcinomas (CCC), transitional-cell Brenner tumors, mixed, and undifferentiated type [2]. Standard treatment for ovarian cancer includes restriction surgery and chemotherapy, while the effectiveness of these therapies is around 80–90%, most of the patients will develop into chemotherapy resistance and the 5-year survival rate is around 35% [3]. Pazopanib is the inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and stem cell receptor (c-Kit), and has been approved in the treatment of renal cell carcinoma and soft tissue carcinoma [4–6], via inhibition of angiogenesis, proliferation and metastasis processes of cancer cells. A recent study explored the efficacy and tolerability of pazopanib in ovarian cancer. According to the results of the experiment, pazopanib improved the overall survival rate of ovarian cancer patients, however, the toxicity of pazopanib presented at a dose of 800 mg daily [7]. However, the detailed mechanism of pazopanib in the treatment of ovarian cancer was not clear yet, and the reduction of pazopanib dose might be helpful to reduce the toxicity effect. N-myc downstream-regulated gene 2 (NDRG2) is an important member of the NDRG family, which is located at chromosome 14q11.2. A previous study indicated that NDRG2 is a tumor suppressor gene via regulation of cellular metabolic processes, including ion, hormone, and fluid as well as hypoxia and lipotoxicity [8–10].