TP53 | Cancer Genetics Web

Chronic Lymphocytic Leukemia (CLL)

MicroRNAs

SIRT1

Li XT, Zhu HY, Wang L, et al.
[Survival analysis of 118 chronic lymphocytic leukemia patients with abnormal TP53 gene in the era of traditional immunochemotherapy].
Zhonghua Xue Ye Xue Za Zhi. 2019; 40(5):378-383 [PubMed] Related Publications

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CLL - Molecular Biology

Chen ZH, Luo NY, Ren XH, et al.
[Analysis of the potential role of SET in chromium-induced malignant transformation cells based on quantitative proteomics].
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2019; 37(3):169-173 [PubMed] Related Publications

Related:

SET

Kumar KJS, Vani MG, Hsieh HW, et al.
Antcin-A Modulates Epithelial-to-Mesenchymal Transition and Inhibits Migratory and Invasive Potentials of Human Breast Cancer Cells via p53-Mediated miR-200c Activation.
Planta Med. 2019; 85(9-10):755-765 [PubMed] Related Publications

Antcin-A (ATA) is a steroid-like phytochemical isolated from the fruiting bodies of a precious edible mushroom

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MicroRNAs

TGFB1

CDH1

Jung YY, Woo HY, Kim HS
Targeted Genomic Sequencing Reveals Novel
Anticancer Res. 2019; 39(6):2883-2889 [PubMed] Related Publications

BACKGROUND/AIM: High-grade serous carcinoma (HGSC) is the most common histological subtype of ovarian carcinoma. Somatic mutation of tumor protein 53 (TP53) is a hallmark of tubo-ovarian HGSC and is observed in almost all such cases. Highly sensitive targeted genomic sequencing can be used to identify novel mutations that may become potential druggable targets and aid in therapeutic decisions. The aim of this study was to describe the clinicopathological and molecular characteristics of HGSCs with novel somatic TP53 mutations identified by next-generation sequencing (NGS).
MATERIALS AND METHODS: A commercial NGS panel comprising 170 genes, including TP53, was used to analyze the genetic profiles of 132 ovarian carcinoma cases. The clinicopathological characteristics and p53 immunostaining results of two HGSCs exhibiting novel TP53 mutations were investigated.
RESULTS: Eighty-eight (66.7%) out of 132 ovarian carcinoma cases were diagnosed as HGSC. Novel TP53 in-frame deletion mutations c.719_727delGTTCCTGCA (p53 p.Ser240_Cys242del) and c.634_642delTTTCGACAT (p53 p.F212_H214del) were detected in a single case of HGSC each. Both patients were postmenopausal women. Imaging and laboratory studies revealed peritoneal carcinomatosis and elevated levels of serum tumor markers. The patients underwent primary debulking surgery and were diagnosed as having stage IIIC HGSC. In both cases, p53 immunostaining revealed uniform nuclear immunoreactivity in 90% or more of tumor cells at a very strong intensity.
CONCLUSION: Targeted genomic sequencing revealed novel in-frame deletion mutations of TP53 leading to p53 overexpression in tubo-ovarian HGSC. This discovery of previously unreported somatic TP53 mutations provides insight into the translation of NGS technology into personalized medicine and identifies new potential targets for therapeutic applications.

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Fallopian Tube Cancer

Ovarian Cancer

Yoshii S, Hayashi Y, Iijima H, et al.
Exosomal microRNAs derived from colon cancer cells promote tumor progression by suppressing fibroblast TP53 expression.
Cancer Sci. 2019; 110(8):2396-2407 [PubMed] Free Access to Full Article Related Publications

The tumor microenvironment offers favorable conditions for tumor progression, and activated fibroblasts, known as cancer-associated fibroblasts, play a pivotal role. TP53-deficient cancer cells are known to induce strong fibroblast activation. We aimed to elucidate the oncogenic role of exosomes derived from TP53-deficient colon cancer cells in fibroblast proliferation and tumor growth. Cancer cell-derived exosomes (CDEs) were isolated from the conditioned media of cancer cells using a sequential ultracentrifugation method. The effects of exosomes on tumor growth were evaluated using human cell lines (TP53-WT colon cancer, HCT116; TP53-mutant colon cancer, HT29; and fibroblasts, CCD-18Co and WI-38) and an immune-deficient nude mouse xenograft model. HCT116 (HCT116

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MicroRNAs

Zhao J, Chen HQ, Yang HF, et al.
Epigenetic silencing of ALX4 regulates microcystin-LR induced hepatocellular carcinoma through the P53 pathway.
Sci Total Environ. 2019; 683:317-330 [PubMed] Related Publications

Recent studies have shown that microcystin-LR (MC-LR) is one of the principal factors that cause liver cancer. Previously we have found that Aristaless-like Homeobox 4 (ALX4) was differentially expressed in MC-LR-induced malignant transformed L02 cells. However, the expression regulation, role and molecular mechanism of ALX4 during the process of liver cancer induced by MC-LR are still unclear. The expression of ALX4 was detected by quantitative reverse-transcription PCR and Western blot in MC-LR induced malignantly transformed cell and rat models. Methylation status of ALX4 promoter region was evaluated by methylation-specific PCR and bisulfite genomic sequencing. The anti-tumor effects of ALX4 on MC-LR induced liver cancer were identified in vitro and in vivo. ALX4 expression was progressively down-regulated in MC-LR-induced malignantly transformed L02 cells and the MC-LR exposed rat models. ALX4 promoter regions were highly methylated in malignantly transformed cells, while treatment with demethylation agent 5-aza-dC significantly increased ALX4 expression. Functional studies showed that overexpression of ALX4 inhibits cell proliferation, migration, invasion and metastasis in vitro and in vivo, blocks the G1/S phase and promotes the apoptosis. Conversely, knockdown of ALX4 promotes cell proliferation, migration and invasion. Mechanism study found that ALX4 exerts its antitumor function through the P53 pathway, C-MYC and MMP9. More importantly, ALX4 expression level showed a negative relation with serum MC-LR levels in patients with hepatocellular carcinoma. Our results suggested that ALX4 was inactivated by DNA methylation and played a tumor suppressor function through the P53 pathway in MC-LR induced liver cancer.

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Liver Cancer

Shao L, Zuo X, Yang Y, et al.
The inherited variations of a p53-responsive enhancer in 13q12.12 confer lung cancer risk by attenuating TNFRSF19 expression.
Genome Biol. 2019; 20(1):103 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: Inherited factors contribute to lung cancer risk, but the mechanism is not well understood. Defining the biological consequence of GWAS hits in cancers is a promising strategy to elucidate the inherited mechanisms of cancers. The tag-SNP rs753955 (A>G) in 13q12.12 is highly associated with lung cancer risk in the Chinese population. Here, we systematically investigate the biological significance and the underlying mechanism behind 13q12.12 risk locus in vitro and in vivo.
RESULTS: We characterize a novel p53-responsive enhancer with lung tissue cell specificity in a 49-kb high linkage disequilibrium block of rs753955. This enhancer harbors 3 highly linked common inherited variations (rs17336602, rs4770489, and rs34354770) and six p53 binding sequences either close to or located between the variations. The enhancer effectively protects normal lung cell lines against pulmonary carcinogen NNK-induced DNA damages and malignant transformation by upregulating TNFRSF19 through chromatin looping. These variations significantly weaken the enhancer activity by affecting its p53 response, especially when cells are exposed to NNK. The effect of the mutant enhancer alleles on TNFRSF19 target gene in vivo is supported by expression quantitative trait loci analysis of 117 Chinese NSCLC samples and GTEx data. Differentiated expression of TNFRSF19 and its statistical significant correlation with tumor TNM staging and patient survival indicate a suppressor role of TNFRSF19 in lung cancer.
CONCLUSION: This study provides evidence of how the inherited variations in 13q12.12 contribute to lung cancer risk, highlighting the protective roles of the p53-responsive enhancer-mediated TNFRSF19 activation in lung cells under carcinogen stress.

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Cancer Screening and Early Detection

Chromosome 13

Lung Cancer

Holzer K, Ori A, Cooke A, et al.
Nucleoporin Nup155 is part of the p53 network in liver cancer.
Nat Commun. 2019; 10(1):2147 [PubMed] Free Access to Full Article Related Publications

Cancer-relevant signalling pathways rely on bidirectional nucleocytoplasmic transport events through the nuclear pore complex (NPC). However, mechanisms by which individual NPC components (Nups) participate in the regulation of these pathways remain poorly understood. We discover by integrating large scale proteomics, polysome fractionation and a focused RNAi approach that Nup155 controls mRNA translation of p21 (CDKN1A), a key mediator of the p53 response. The underlying mechanism involves transcriptional regulation of the putative tRNA and rRNA methyltransferase FTSJ1 by Nup155. Furthermore, we observe that Nup155 and FTSJ1 are p53 repression targets and accordingly find a correlation between the p53 status, Nup155 and FTSJ1 expression in murine and human hepatocellular carcinoma. Our data suggest an unanticipated regulatory network linking translational control by and repression of a structural NPC component modulating the p53 pathway through its effectors.

Related:

CDKN1A

Liver Cancer

Gruffaz M, Yuan H, Meng W, et al.
CRISPR-Cas9 Screening of Kaposi's Sarcoma-Associated Herpesvirus-Transformed Cells Identifies XPO1 as a Vulnerable Target of Cancer Cells.
MBio. 2019; 10(3) [PubMed] Free Access to Full Article Related Publications

The abnormal proliferation of cancer cells is driven by deregulated oncogenes or tumor suppressors, among which the cancer-vulnerable genes are attractive therapeutic targets. Targeting mislocalization of oncogenes and tumor suppressors resulting from aberrant nuclear export is effective for inhibiting growth transformation of cancer cells. We performed a clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) screening in a unique model of matched primary and oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV)-transformed cells and identified genes that were growth promoting and growth suppressive for both types of cells, among which exportin XPO1 was demonstrated to be critical for the survival of transformed cells. Using XPO1 inhibitor KPT-8602 and by small interfering RNA (siRNA) knockdown, we confirmed the essential role of XPO1 in cell proliferation and growth transformation of KSHV-transformed cells and in cell lines of other cancers, including gastric cancer and liver cancer. XPO1 inhibition induced cell cycle arrest through p53 activation, but the mechanisms of p53 activation differed among the different types of cancer cells. p53 activation depended on the formation of promyelocytic leukemia (PML) nuclear bodies in gastric cancer and liver cancer cells. Mechanistically, XPO1 inhibition induced relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. Taken the data together, we have identified novel growth-promoting and growth-suppressive genes of primary and cancer cells and have demonstrated that XPO1 is a vulnerable target of cancer cells. XPO1 inhibition induces cell arrest through a novel PML- and p62-dependent mechanism of p53 activation in some types of cancer cells.

Related:

Liver Cancer

Stomach Cancer

Gastric Cancer

SQSTM1

Wujcicka W, Zając A, Stachowiak G
Impact of
In Vivo. 2019 May-Jun; 33(3):917-924 [PubMed] Free Access to Full Article Related Publications

BACKGROUND/AIM: The aim of this study was to determine the joint effect of single nucleotide polymorphisms (SNPs) of MDM2, TP53, and CDKN2A (P14ARF) genes on the onset and course of endometrial cancer (EC) in postmenopausal women.
MATERIALS AND METHODS: The study group consisted of 144 EC women and 50 non-cancer controls. MDM2 rs22279744, TP53 rs1042522, and P14ARF rs3088440, rs3731217, and rs3731245 SNPs were analysed.
RESULTS: The double-SNP combinations T-C, T-T, or T-G in MDM2 SNP 309 and P14ARF polymorphisms decreased EC risk. The triple-SNP combinations T-C-T, T-C-G, or T-T-G in MDM2 SNP and two P14ARF polymorphisms decreased EC risk. The multiple-SNP combination T-C-T-G in MDM2 and three P14ARF polymorphisms decreased EC risk. The G-Arg-C-T-G carriers were at increased EC risk, while the T-Arg-C-T-G carriers were at decreased EC risk.
CONCLUSION: MDM2 SNP309 plays a role in EC onset in postmenopausal women.

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Endometrial (Uterus) Cancer

Endometrial Cancer

MDM2

Wu AY, Gu LY, Cang W, et al.
Fn14 overcomes cisplatin resistance of high-grade serous ovarian cancer by promoting Mdm2-mediated p53-R248Q ubiquitination and degradation.
J Exp Clin Cancer Res. 2019; 38(1):176 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: High-grade serous ovarian cancer (HGSOC) is the most lethal of all gynecological malignancies. Patients often suffer from chemoresistance. Several studies have reported that Fn14 could regulate migration, invasion, and angiogenesis in cancer cells. However, its functional role in chemoresistance of HGSOC is still unknown.
METHODS: The expression of Fn14 in tissue specimens was detected by IHC. CCK-8 assay was performed to determine changes in cell viability. Apoptosis was measured by flow cytometry. The potential molecular mechanism of Fn14-regulated cisplatin resistance in HGSOC was investigated using qRT-PCR, western blotting, and Co-IP assays. The role of Fn14 in HGSOC was also investigated in a xenograft mouse model.
RESULTS: In this study, we found that Fn14 was significantly downregulated in patients with cisplatin resistance. Patients with low Fn14 expression were associated with shorter progression-free survival and overall survival. Overexpression of Fn14 suppressed cisplatin resistance in OVCAR-3 cells, whereas knockdown of Fn14 did not affect cisplatin resistance in SKOV-3 cells. Interestingly, Fn14 could exert anti-chemoresistance effect only in OVCAR-3 cells harboring a p53-R248Q mutation, but not in SKOV-3 cells with a p53-null mutation. We isolated and identified primary cells from two patients with the p53-R248Q mutation from HGSOC patients and the anti-chemoresistance effect of Fn14 was observed in both primary cells. Mechanistic studies demonstrated that overexpression of Fn14 could reduce the formation of a Mdm2-p53-R248Q-Hsp90 complex by downregulating Hsp90 expression, indicating that degradation of p53-R248Q was accelerated via Mdm2-mediated ubiquitin-proteasomal pathway.
CONCLUSION: Our findings demonstrate for the first time that Fn14 overcomes cisplatin resistance through modulation of the degradation of p53-R248Q and restoration of Fn14 expression might be a novel strategy for the treatment of HGSOC.

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Song Z, Yin Y, Hao S, et al.
JS‑K induces G2/M phase cell cycle arrest and apoptosis in A549 and H460 cells via the p53/p21WAF1/CIP1 and p27KIP1 pathways.
Oncol Rep. 2019; 41(6):3475-3487 [PubMed] Related Publications

Lung cancer is one of the most common malignancies worldwide, with high mortality and morbidity rates. O2‑(2,4‑dinitrophenyl)‑1‑[(4‑ethoxycarbonyl)piperazin‑1‑yl]diazen‑1‑ium‑1,2‑diolate (JS‑K) is a potent anticancer agent that acts against a subset of human non‑small cell lung cancer (NSCLC) cell lines; however, the underlying mechanisms of JS‑K in NSCLC remain unclear. The present study aimed to evaluate the anticancer effect of JS‑K and investigate its underlying mechanisms in A549 and H460 cells. In the present study, A549 and H460 cells were treated with JS‑K, and then evaluated by cell viability assay, flow cytometry and western blot analysis. JS‑K markedly induced cell cycle arrest at the G2/M phase in a concentration and time‑dependent manner in both cell lines. This was associated with increased expression levels of p53, and the cell cycle inhibitors p21WAF1/CIP1 and p27KIP1, which, in turn, inhibited the expression of Cdc2, cyclin B1 and cyclin‑dependent kinase 2. In addition, JS‑K‑induced inhibition of proliferation was revealed to be partially modulated by the upregulation of p53 and p21WAF1, the ratio of Bax/Bcl‑2, and the activation of both the intrinsic and extrinsic apoptotic pathways in A549 and H460 cells. These results demonstrated that JS‑K could trigger cell cycle arrest at the G2/M phase and apoptosis in A549 and H460 cells, which was likely mediated via the p53/p21WAF1/CIP1 and p27KIP1 pathways. Overall, the results indicated that JS‑K may be used as an anticancer agent for the treatment of NSCLC.

Related:

Non-Small Cell Lung Cancer

CDKN1A

CDKN1B

Valletti A, Marzano F, Pesole G, et al.
Targeting Chemoresistant Tumors: Could TRIM Proteins-p53 Axis Be a Possible Answer?
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications

Chemosensitivity is a crucial feature for all tumours so that they can be successfully treated, but the huge heterogeneity of these diseases, to be intended both inter- and intra-tumour, makes it a hard-to-win battle. Indeed, this genotypic and phenotypic variety, together with the adaptability of tumours, results in a plethora of chemoresistance acquisition mechanisms strongly affecting the effectiveness of treatments at different levels. Tripartite motif (TRIM) proteins are shown to be involved in some of these mechanisms thanks to their E3-ubiquitin ligase activity, but also to other activities they can exert in several cellular pathways. Undoubtedly, the ability to regulate the stability and activity of the p53 tumour suppressor protein, shared by many of the TRIMs, represents the preeminent link between this protein family and chemoresistance. Indeed, they can modulate p53 degradation, localization and subset of transactivated target genes, shifting the cellular response towards a cytoprotective or cytotoxic reaction to whatever damage induced by therapy, sometimes in a cellular-dependent way. The involvement in other chemoresistance acquisition mechanisms, independent by p53, is known, affecting pivotal processes like PI3K/Akt/NF-κB signalling transduction or Wnt/beta catenin pathway, to name a few. Hence, the inhibition or the enhancement of TRIM proteins functionality could be worth investigating to better understand chemoresistance and as a strategy to increase effectiveness of anticancer therapies.

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Cancer Prevention and Risk Reduction

AKT1

Cancer Prevention and Risk Reduction

Vozdova M, Kubickova S, Fictum P, et al.
Prevalence and prognostic value of c-kit and TP53 mutations in canine mast cell tumours.
Vet J. 2019; 247:71-74 [PubMed] Related Publications

Cutaneous mast cell tumours (MCT) are among the most frequent malignancies in dogs. Their clinical behaviour is highly variable and, with the exception of mutations in the c-kit gene, little is known about their genetic aetiology. The mutational status of the c-kit exons 8, 9 and 11, and exons 5-8 of the TP53 gene was analysed to find markers for molecular stratification of MCTs and predictors of clinical outcome. Mutations in the c-kit gene were detected in 19.5% (n = 8/41) samples and their presence was significantly associated with the high histopathological grade (P = 0.038). Mutations in the DNA binding domain of the TP53 gene were found in 14.6% (n = 6/41) of the analysed MCTs, and their frequency was similar in low and high grade MCTs (P > 0.05). TP53 mutations were not useful prognostic factors in this sample of canine cutaneous MCTs.

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Skin Cancer

Oppel F, Tao T, Shi H, et al.
Loss of atrx cooperates with p53-deficiency to promote the development of sarcomas and other malignancies.
PLoS Genet. 2019; 15(4):e1008039 [PubMed] Free Access to Full Article Related Publications

The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously reported p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation of atrx using CRISPR/Cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. In p53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset in atrx+/- fish, but these fish developed various tumors that were not observed in their atrx+/+ siblings, including epithelioid sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and rare types of carcinoma. These cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably mimics a role for ATRX-loss in the early pathogenesis of these human cancer types. RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples. Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development.

Related:

ATRX

Olszewski MB, Pruszko M, Snaar-Jagalska E, et al.
Diverse and cancer type‑specific roles of the p53 R248Q gain‑of‑function mutation in cancer migration and invasiveness.
Int J Oncol. 2019; 54(4):1168-1182 [PubMed] Free Access to Full Article Related Publications

Gain‑of‑function (GOF) mutations in the TP53 gene lead to acquisition of new functions by the mutated tumor suppressor p53 protein. A number of the over‑represented 'hot spot' mutations, including the ones in codons 175, 248 or 273, convey GOF phenotypes. Such phenotypes may include resistance to chemotherapeutics or changes in motility and invasiveness. Whereas the prevalent notion is that the acquisition of the p53 GOF phenotype translates into poorer prognosis for the patient, the analysis of a human somatic p53 mutations dataset demonstrated earlier tumor onset, but decreased frequency and altered location of metastases in patients with the p53‑R248Q allele. Therefore, the GOF activities of p53‑R248Q and p53‑D281G were analyzed in triple negative breast cancer MDA‑MB‑231 and lung adenocarcinoma H1299 cell lines with regard to invasive and metastatic traits. The expression of p53‑D281G increased the motility and invasiveness of the lung cancer cells, but not those of the breast cancer cells. In contrast, the expression of p53‑R248Q decreased the motility and invasiveness of the breast and lung cancer cells in a p53 transactivation‑dependent manner. The intravenous xenotransplantation of MDA‑MB‑231 cells expressing p53‑R248Q into zebrafish embryos resulted in an alteration of the distribution of cancer cells in the body of the fish. In p53‑R248Q‑expressing H1299 cells a decrease in the expression of TCF8/ZEB1 and N‑cadherin was observed, suggesting partial mesenchymal‑to‑epithelial transition. In the two cell lines expressing p53‑R248Q a decrease was noted in the expression of myosin light chain 2, a protein involved in actomyosin‑based motility. To the best of our knowledge, the present study is one of only few reports demonstrating the mutated p53 GOF activity resulting in a decrease of a malignant trait in human cancer.

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Chu B, Kon N, Chen D, et al.
ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway.
Nat Cell Biol. 2019; 21(5):579-591 [PubMed] Article available free on PMC after 08/10/2019 Related Publications

It is well established that ferroptosis is primarily controlled by glutathione peroxidase 4 (GPX4). Surprisingly, we observed that p53 activation modulates ferroptotic responses without apparent effects on GPX4 function. Instead, ALOX12 inactivation diminishes p53-mediated ferroptosis induced by reactive oxygen species stress and abrogates p53-dependent inhibition of tumour growth in xenograft models, suggesting that ALOX12 is critical for p53-mediated ferroptosis. The ALOX12 gene resides on human chromosome 17p13.1, a hotspot of monoallelic deletion in human cancers. Loss of one Alox12 allele is sufficient to accelerate tumorigenesis in Eμ-Myc lymphoma models. Moreover, ALOX12 missense mutations from human cancers abrogate its ability to oxygenate polyunsaturated fatty acids and to induce p53-mediated ferroptosis. Notably, ALOX12 is dispensable for ferroptosis induced by erastin or GPX4 inhibitors; conversely, ACSL4 is required for ferroptosis upon GPX4 inhibition but dispensable for p53-mediated ferroptosis. Thus, our study identifies an ALOX12-mediated, ACSL4-independent ferroptosis pathway that is critical for p53-dependent tumour suppression.

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Lin F, Xie YJ, Zhang XK, et al.
GTSE1 is involved in breast cancer progression in p53 mutation-dependent manner.
J Exp Clin Cancer Res. 2019; 38(1):152 [PubMed] Article available free on PMC after 08/10/2019 Related Publications

BACKGROUND: With the rapid development of the high throughput detection techniques, tumor-related Omics data has become an important source for studying the mechanism of tumor progression including breast cancer, one of the major malignancies worldwide. A previous study has shown that the G2 and S phase-expressed-1 (GTSE1) can act as an oncogene in several human cancers. However, its functional roles in breast cancer remain elusive.
METHOD: In this study, we analyzed breast cancer data downloaded from The Cancer Genome Atlas (TCGA) databases and other online database including the Oncomine, bc-GenExMiner and PROGgeneV2 database to identify the molecules contributing to the progression of breast cancer. The GTSE1 expression levels were investigated using qRT-PCR, immunoblotting and IHC. The biological function of GTSE1 in the growth, migration and invasion of breast cancer was examined in MDA-MB-231, MDA-MB-468 and MCF7 cell lines. The in vitro cell proliferative, migratory and invasive abilities were evaluated by MTS, colony formation and transwell assay, respectively. The role of GTSE1 in the growth and metastasis of breast cancer were revealed by in vivo investigation using BALB/c nude mice.
RESULTS: We showed that the expression level of GTSE1 was upregulated in breast cancer specimens and cell lines, especially in triple negative breast cancer (TNBC) and p53 mutated breast cancer cell lines. Importantly, high GTSE1 expression was positively correlated with histological grade and poor survival. We demonstrated that GTSE1 could promote breast cancer cell growth by activating the AKT pathway and enhance metastasis by regulating the Epithelial-Mesenchymal transition (EMT) pathway. Furthermore, it could cause multidrug resistance in breast cancer cells. Interestingly, we found that GTSE1 could regulate the p53 function to alter the cell cycle distribution dependent on the mutation state of p53.
CONCLUSION: Our results reveal that GTSE1 played a key role in the progression of breast cancer, indicating that GTSE1 could serve as a novel biomarker to aid in the assessment of the prognosis of breast cancer.

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AKT1

Wan J, Block S, Scribano CM, et al.
Mad1 destabilizes p53 by preventing PML from sequestering MDM2.
Nat Commun. 2019; 10(1):1540 [PubMed] Article available free on PMC after 08/10/2019 Related Publications

Mitotic arrest deficient 1 (Mad1) plays a well-characterized role in the mitotic checkpoint. However, interphase roles of Mad1 that do not impact mitotic checkpoint function remain largely uncharacterized. Here we show that upregulation of Mad1, which is common in human breast cancer, prevents stress-induced stabilization of the tumor suppressor p53 in multiple cell types. Upregulated Mad1 localizes to ProMyelocytic Leukemia (PML) nuclear bodies in breast cancer and cultured cells. The C-terminus of Mad1 directly interacts with PML, and this interaction is enhanced by sumoylation. PML stabilizes p53 by sequestering MDM2, an E3 ubiquitin ligase that targets p53 for degradation, to the nucleolus. Upregulated Mad1 displaces MDM2 from PML, freeing it to ubiquitinate p53. Upregulation of Mad1 accelerates growth of orthotopic mammary tumors, which show decreased levels of p53 and its downstream effector p21. These results demonstrate an unexpected interphase role for Mad1 in tumor promotion via p53 destabilization.

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MDM2

PML

Fan X, Wu X
MicroRNA-122-5p promotes the development of non-small cell lung cancer via downregulating p53 and activating PI3K-AKT pathway.
J BUON. 2019 Jan-Feb; 24(1):273-279 [PubMed] Related Publications

PURPOSE: To investigate the role of microRNA-122-5p in the pathogenesis of non-small cell lung cancer (NSCLC) and its underlying mechanism.
METHODS: A total of 72 pairs of NSCLC tissues and paracancerous tissues were collected. The expression level of microRNA-122-5p in NSCLC tissues and paracancerous tissues were detected by qRT-PCR (quantitative real-time polymerase chain reaction). The relationship between microRNA-122-5p expression and the clinical prognosis of NSCLC patients was then analyzed. Bioinformatics prediction and luciferase activity assay were performed to validate the direct binding of microRNA-122-5p and p53. Cell cycle, proliferation, and apoptosis were detected after microRNA-122-5p knockdown in NSCLC cells. The regulatory effect of microRNA-122-5p on promoting NSCLC development was detected by Western blot.
RESULTS: MicroRNA-122-5p was more overexpressed in NSCLC tissues than in paracancerous tissues. MicroRNA-122-5p expression was negatively correlated with survival rate of NSCLC patients. Besides, microRNA-122-5p knockdown remarkably inhibited the proliferation and cell cycle advancement and increased apoptosis of NSCLC cells. Luciferase reporter gene assay and Western blot results indicated that microRNA-122-5p downregulated p53 and activated PI3K-AKT pathway, thereby promoting NSCLC development.
CONCLUSION: MicroRNA-122-5p is overexpressed in NSCLC. Overexpression of microRNA-122-5p promotes NSCLC development by downregulating p53 and activating PI3K-AKT pathway.

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Non-Small Cell Lung Cancer

Velinovic M, Jankovic R, Jovanovic D, et al.
Tumor characteristics, expressions of ERCC1, Bax, p53, IGF1R, Bcl2, Bcl2/Bax and prognostic factors for overall survival in patients with lung carcinoid.
J BUON. 2019 Jan-Feb; 24(1):256-266 [PubMed] Related Publications

PURPOSE: Neuroendocrine lung tumors (NET) include typical carcinoids (TC), atypical carcinoids (AC), large cell NE carcinoma (LCNEC) and small-cell carcinoma (SCLC), with different clinicopathological profiles and relative grades of malignancy. Although differences between carcinoids and high grade carcinomas are recognized, precise differences and behavior of TC and AC have not been clearly defined. The aim of this study was to better define the differences in the clinical behavior of TC and AC, and to establish new prognostic factors of overall survival (OS), by determining the levels of genetic expression of IGF1R, ERCC1, Bax, p53, Bcl2 and Bcl2/Bax ratio.
METHODS: The histopathological diagnosis of 52 surgically resected pulmonary carcinoid tumors was made according to the WHO classification. Gene expressions were evaluated by quantitative real-time PCR.
RESULTS: The confirmed prognostic factors for overall survival (OS) were pTNM T (p<0.01), pTNM N (p<0.05), clinical stage (p<0.05), type of surgery (p<0.01) and histopathological (HP) tumor type (p<0.05). Bcl2 mRNA level and Bcl2/Bax ratio were found to have a potential for discrimination of the HP type of tumor (AC vs TC, Receiver Operating Characteristics (ROC) cut-off values 0.1451 and 0.3015, respectively), but without statistically significant impact on OS.
CONCLUSIONS: In patients with NETs, smaller primary tumor, absence of positive lymph nodes, and TC type of tumor predicted longer OS. Type of resection has influence on OS. Bcl2 expression and Bcl2/Bax ratio might be valuable as independent diagnostic parametars in lung carcinoids. Therapeutic approaches using attenuation of Bcl2 or upregulation of Bax might prove useful in lung NETs.

Related:

Gastrointestinal Carcinoid Tumours

Carcinoid Tumors

Lung Cancer

ERCC1

Müller M, Graf R, Kashofer K, et al.
Detection of AML-specific TP53 mutations in bone marrow-derived mesenchymal stromal cells cultured under hypoxia conditions.
Ann Hematol. 2019; 98(8):2019-2020 [PubMed] Article available free on PMC after 08/10/2019 Related Publications

Related:

Acute Myeloid Leukemia (AML)

Chung J, Sallman DA, Padron E
TP53 and therapy-related myeloid neoplasms.
Best Pract Res Clin Haematol. 2019; 32(1):98-103 [PubMed] Related Publications

Therapy-related myeloid neoplasms (t-MNs) are the most serious late complications in patients treated with traditional cytotoxic chemotherapy and/or radiation. T-MNs are aggressive and chemorefractory hematologic malignancies, with a median survival of less than 6 months. TP53 mutations are highly enriched in t-MN patients, though the mechanism for this selective enrichment has only come to light over the past several years. In this review, we discuss the history and function of p53, and the role of TP53 mutations in the origin and progression of t-MNs. Emerging data has begun to elucidate who may be at highest risk of developing t-MNs, which ideally will enable us to develop preventative strategies for this devastating disease. As t-MNs may not be avoidable, novel therapies are urgently needed for this patient group and are underway as exemplified by recent investigation in restoring wild-type p53 function as well as directly targeting TP53 mutant variants. With better prevention and treatment, outcomes will hopefully begin to improve in the near future.

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Haematological Malignancies & Realted Disorders

Jeong G, Oh J, Kim JS
Glyceollins Modulate Tumor Development and Growth in a Mouse Xenograft Model of Human Colon Cancer in a
J Med Food. 2019; 22(5):521-528 [PubMed] Related Publications

Glyceollins are soybean-derived phytoalexins that induce the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathway, which is involved in the detoxification of carcinogens and the removal of reactive oxygen species (ROS). Recent studies, however, have indicated that Nrf2 induction stimulates the development of pre-existing tumors and confers resistance to chemotherapy by elevating drug metabolism and by efficient scavenging of ROS produced by the Warburg effect, which is regulated, in turn, by the p53 tumor suppressor. This study, therefore, aimed at examining whether glyceollins could accelerate tumor growth in the presence of active p53, using a xenograft BALB/c nude mouse model transplanted subcutaneously with p53 wild-type and p53 null HCT116 human colon cancer cells. Glyceollins were orally administered at a dose of either 1 or 4 mg/kg body weight after xenografting HCT116 cells, and tumor growth and volume were monitored for 2 weeks. A high dose of glyceollins resulted in a significant increase in the average volume of p53 wild-type HCT116 xenografts, but not of p53 null HCT116 xenografts. However, a low dose of glyceollins had no effect on the tumor growth regardless of p53 presence. Interestingly, antioxidant enzymes, including heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase, were prominently induced by glyceollins in p53 wild-type xenografts, compared with p53 null xenografts. These results suggest that a high dose of glyceollins possibly promotes the growth of p53 wild-type colon cancer through activation of the Nrf2-mediated signaling pathway and, in particular, strong induction of HO-1 expression. Therefore, the consumption of Nrf2 activators, including glyceollins, should be carefully monitored for patients suffering from certain types of cancer and/or receiving chemotherapy.

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NFE2L2