Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: TP53BP2 (cancer-related)
BACKGROUND: Apoptosis-stimulating Protein of TP53-2 (ASPP2) is a tumor suppressor enhancing TP53-mediated apoptosis via binding to the TP53 core domain. TP53 mutations found in cancers disrupt ASPP2 binding, arguing for an important role of ASPP2 in TP53-mediated tumor suppression. We now identify an oncogenic splicing variant, ASPP2κ, with high prevalence in acute leukemia.
METHODS: An mRNA screen to detect ASPP2 splicing variants was performed and ASPP2κ was validated using isoform-specific PCR approaches. Translation into a genuine protein isoform was evaluated after establishing epitope-specific antibodies. For functional studies cell models with forced expression of ASPP2κ or isoform-specific ASPP2κ-interference were created to evaluate proliferative, apoptotic and oncogenic characteristics of ASPP2κ.
FINDINGS: Exon skipping generates a premature stop codon, leading to a truncated C-terminus, omitting the TP53-binding sites. ASPP2κ translates into a dominant-negative protein variant impairing TP53-dependent induction of apoptosis. ASPP2κ is expressed in CD34+ leukemic progenitor cells and functional studies argue for a role in early oncogenesis, resulting in perturbed proliferation and impaired induction of apoptosis, mitotic failure and chromosomal instability (CIN) - similar to TP53 mutations. Importantly, as expression of ASPP2κ is stress-inducible it defines a novel class of dynamic oncogenes not represented by genomic mutations.
INTERPRETATION: Our data demonstrates that ASPP2κ plays a distinctive role as an antiapoptotic regulator of the TP53 checkpoint, rendering cells to a more aggressive phenotype as evidenced by proliferation and apoptosis rates - and ASPP2κ expression results in acquisition of genomic mutations, a first initiating step in leukemogenesis. We provide proof-of-concept to establish ASPP2κ as a clinically relevant biomarker and a target for molecule-defined therapy. FUND: Unrestricted grant support from the Wilhelm Sander Foundation for Cancer Research, the IZKF Program of the Medical Faculty Tübingen, the Brigitte Schlieben-Lange Program and the Margarete von Wrangell Program of the State Ministry Baden-Wuerttemberg for Science, Research and Arts and the Athene Program of the excellence initiative of the Eberhard-Karls University, Tübingen.
Zhu M, Wu J, Ma X, et al.Butyl benzyl phthalate promotes prostate cancer cell proliferation through miR-34a downregulation.
Toxicol In Vitro. 2019; 54:82-88 [PubMed
] Related Publications
Prostate cancer is the most common malignancy in men. Phthalate esters are a class of environmental endocrine disruptors and were reported to be cancer promoting agents, however the potential role of phthalate esters in prostate cancer has been rarely reported. Mounting evidence has shown that miR-34a is a master tumor suppressor miRNA in cancer. The aim of this study was to investigate the role of butyl benzyl phthalate (BBP), one of the typical phthalate esters, in cell proliferation of prostate cancer cells. Human prostate cancer LNCaP and PC-3 cells were exposed to low dose of BBP for 6 days. The results showed that 10
Zhu M, Huang C, Ma X, et al.Phthalates promote prostate cancer cell proliferation through activation of ERK5 and p38.
Environ Toxicol Pharmacol. 2018; 63:29-33 [PubMed
] Related Publications
Prostate cancer is one of the most commonly diagnosed cancers in man. Studies have shown that phthalates may act as promoters in various types of cancer; however, the role of phthalates in prostate cancer has been rarely reported. The MAPK/AP-1 pathway is a vital regulator of cell proliferation in cancer. In this report we found that three typical phthalates, diethylhexyl phthalate (DEHP), Butyl benzyl phthalate (BBP) and Dibutyl phthalate (DBP), up-regulated cyclinD1 and PCNA, down-regulated P21, inducing proliferation of prostate cancer cells. Furthermore, we found that phthalates increased the expression of p-ERK5 and p-p38, along with upregulation of AP-1 (p-c-fos and p-c-jun). In studies with ERK5 and a p38 inhibitor, our data showed that downregulation of p-ERK5 or p38 inhibited phthalate-triggered cell proliferation. Taken together, findings from this study suggest that phthalates activate MAPK/AP-1 pathway and may potentially promote cell proliferation in prostate cancer, thus providing new insight into the effects and the underlying mechanism of phthalates on prostate cancer.
Wu J, Jiang Y, Cao W, et al.miR-19 targeting of PTEN mediates butyl benzyl phthalate-induced proliferation in both ER(+) and ER(-) breast cancer cells.
Toxicol Lett. 2018; 295:124-133 [PubMed
] Related Publications
Breast cancer is the most common cancer among women worldwide. Butyl benzyl phthalate (BBP) is ubiquitous in human's environment, and is strongly linked to breast cancer development. microRNA (miRNA) is an important regulator of target genes. So far, no studies have been reported yet to reveal the action of miRNAs in BBP-mediated breast cancer cell proliferation. In this study, we showed that BBP induced proliferation of both ER(+) MCF-7 and ER(-) MDA-MB-231 breast cancer cells, proved by increased cell viability, transition of cell cycle from G1 to S phase, upregulation of proliferating cell nuclear antigen (PCNA) and Cyclin D1, and downregulation of p21. Meanwhile, the expression of oncogenic miR-19a/b and PTEN/AKT/p21 axis was also modulated by BBP. Furthermore, for the first time we revealed that miR-19 played crucial role in the promoting effect of BBP on breast cancer cells through targeting PTEN 3'UTR. Findings from this study could provide an important new perspective on the molecular mechanisms through which BBP exerts its promoting effect on breast cancer as well as its target intervention.
Liu B, Yang L, Li XJ, et al.Expression and significance of ASPP2 in squamous carcinoma of esophagus.
Kaohsiung J Med Sci. 2018; 34(6):321-329 [PubMed
] Related Publications
To study the significance of apoptosis stimulating protein of P53 2 (ASPP2) expression in esophageal squamous cell carcinoma (ESCC), immunohistochemistry S-P method was used to examine the expression of ASPP2 in 136 cases of ESCC, 35 cases of high grade intraepithelial neoplasia (HGIN), 29 cases of low grade intraepithelial neoplasia (LGIN) and 37 cases of normal esophageal epithelium (NEE). The associations of ASPP2 expression with clinicopathological data and overall survival (OS) were also analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate ASPP2 expression in a total of 20 matched human ESCC tumor tissues and normal adjacent tissues (NAT). In addition, EC109 cells were treated with cisplatin (CDDP) in vitro for 24 h (the intervention group) and the control group was set up at the same time. Western blot was used to examine the expression of ASPP2 protein between the two groups. The expression of ASPP2 decreased progressively from NEE to LGIN, to HGIN, and to ESCC, and it was related to TNM stage, histological differentiation and lymph node metastasis in ESCC (P < 0.05). ASPP2 was a protective factor of patients with ESCC (P = 0.008). The relative expression of ASPP2 mRNA was markedly downregulated in ESCC compared with the paired NAT (P < 0.01). Western blot results showed that cells in the intervention group could express ASPP2 while there was no expression of ASPP2 in the control group. Taken together, these results indicate that the abnormal expression of ASPP2 may play an important role for development and metastasis in ESCC.
Wu T, Song H, Xie D, et al.Silencing of ASPP2 promotes the proliferation, migration and invasion of triple-negative breast cancer cells via the PI3K/AKT pathway.
Int J Oncol. 2018; 52(6):2001-2010 [PubMed
] Related Publications
Apoptosis-stimulating p53 protein 2 (ASPP2) is an apoptosis inducer that acts via binding with p53 and then enhancing the transcriptional activities toward pro‑apoptosis genes. ASPP2 has recently been reported to serve a major role in p53‑independent pathways. Triple‑negative breast cancer (TNBC) is a type of breast cancer that is more aggressive and highly lethal when p53 is mutated. In the present study, the mRNA level of ASPP2 was found to be suppressed in breast tumors compared with that in adjacent normal breast tissues, and the expression of ASPP2 was also decreased in a series of breast cancer cell lines compared with that in MCF‑10A normal breast cells. Downregulation of ASPP2 by specific small interfering RNA (siRNA) transfection was able to promote cell growth, reduce cell apoptosis, and contribute to cell migration and invasion. Furthermore, downregulation of ASPP2 promoted cell epithelial‑mesenchymal transition (EMT) in MDA‑MB‑231 and HCC‑1937 TNBC cells. Furthermore, it was found that when ASPP2 siRNA was transfected into MDA‑MB‑231 and HCC‑1937 cells, the expression of phosphoinositide‑3‑kinase regulatory subunit 1 (p85α) decreased and phosphorylation of protein kinase B (AKT) increased, which are key molecular regulators in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. In conclusion, the present data indicated that ASPP2 had a crucial influence on the proliferation and metastasis in TNBC, and that the functional mechanism may be p53‑independent to a great extent. ASPP2 and its link with the PI3K/AKT pathway deserve further investigation and may provide novel insights into therapeutic targets for TNBC.
BACKGROUND: Carotid body tumor (CBT) is a form of head and neck paragangliomas (HNPGLs) arising at the bifurcation of carotid arteries. Paragangliomas are commonly associated with germline and somatic mutations involving at least one of more than thirty causative genes. However, the specific functionality of a number of these genes involved in the formation of paragangliomas has not yet been fully investigated.
METHODS: Exome library preparation was carried out using Nextera® Rapid Capture Exome Kit (Illumina, USA). Sequencing was performed on NextSeq 500 System (Illumina).
RESULTS: Exome analysis of 52 CBTs revealed potential driver mutations (PDMs) in 21 genes: ARNT, BAP1, BRAF, BRCA1, BRCA2, CDKN2A, CSDE1, FGFR3, IDH1, KIF1B, KMT2D, MEN1, RET, SDHA, SDHB, SDHC, SDHD, SETD2, TP53BP1, TP53BP2, and TP53I13. In many samples, more than one PDM was identified. There are also 41% of samples in which we did not identify any PDM; in these cases, the formation of CBT was probably caused by the cumulative effect of several not highly pathogenic mutations. Estimation of average mutation load demonstrated 6-8 mutations per megabase (Mb). Genes with the highest mutation rate were identified.
CONCLUSIONS: Exome analysis of 52 CBTs for the first time revealed the average mutation load for these tumors and also identified potential driver mutations as well as their frequencies and co-occurrence with the other PDMs.
One of the most common head and neck cancers is laryngeal squamous cell carcinoma (LSCC). LSCC exhibits high mortality rates and has a poor prognosis. The molecular mechanisms leading to the development and progression of LSCC are not entirely clear despite genetic and therapeutic advances and increased survival rates. In this study, a total of 116 differentially expressed genes (DEGs), including 11 upregulated genes and 105 downregulated genes, were screened from LSCC samples and compared with adjacent noncancerous. Statistically significant differences (log 2-fold difference > 0.5 and adjusted P-value < .05) were found in this study in the expression between tumor and nontumor larynx tissue samples. Nine cancer hub genes were found to have a high predictive power to distinguish between tumor and nontumor larynx tissue samples. Interestingly, they also appear to contribute to the progression of LSCC and malignancy via the Jak-STAT signaling pathway and focal adhesion. The model could separate patients into high-risk and low-risk groups successfully when only using the expression level of mRNA signatures. A total of 4 modules (blue, gray, turquoise, and yellow) were screened for the DEGs in the weighted co-expression network. The blue model includes cancer-specific pathways such as pancreatic cancer, bladder cancer, nonsmall cell lung cancer, colorectal cancer, glioma, Hippo signaling pathway, melanoma, chronic myeloid leukemia, prostate cancer, and proteoglycans in cancer. Endocrine resistance (CCND1, RAF1, RB1, and SMAD2) and Hippo signaling pathway (CCND1, LATS1, SMAD2, and TP53BP2) could be of importance in LSCC, because they had high connectivity degrees in the blue module. Results from this study provide a powerful biomarker discovery platform to increase understanding of the progression of LSCC and to reveal potential therapeutic targets in the treatment of LSCC. Improved monitoring of LSCC and resulting improvement of treatment of LSCC might result from this information.
Liu X, Xu J, Wang S, et al.Synergistic inhibitory effects on hepatocellular carcinoma with recombinant human adenovirus Aspp2 and oxaliplatin via p53-independent pathway in vitro and in vivo.
Int J Oncol. 2017; 51(4):1291-1299 [PubMed
] Related Publications
The present study was designed to investigate the synergistic inhibitory effects on hepatocellular carcinoma with recombinant human adenovirus Aspp2 (Aspp2-ad) and oxaliplatin via p53-independent pathway in vitro and in vivo. After being treated with Aspp2-ad and/or oxaliplatin for 24-48 h, HepG2P53-/- and Hep3B cells showed a significant growth inhibition compared with vehicle control. Combination group showed a synergetic effect, the inhibitory rates were all above 80% at 48 h point in HepG2P53-/- and Hep3B cells. The apoptotic cell numbers of Aspp2-ad and/or oxaliplatin treatment groups were increased remarkably, especially for the combined therapy group in the liver cancer cells. The Hep3B xenograft experiment also showed similar inhibition of Aspp2-ad and/or oxaliplatin to the in vitro experiment. H&E results showed that combination group had the least mitotic indexes and the most necrosis. The immunohistochemistry results showed that PCNA, CD31 expression decreased greatly in treatment groups. These results suggested that Aspp2-ad might inhibit proliferation and vascular growth of hepatocarcinoma. Aspp2 induced apoptosis protein expression in Aspp2-ad and combination groups, the Aspp2, Bax and activation of caspase-3 expression increased greatly both in vitro and in vivo. But interestingly, the autophagy proteins showed different responses not only in HepG2P53-/- and Hep3B cells but also in vitro and in vivo. We found that Aspp2-ad downregulated the p-ERK, p-STAT3 expression, the synergistic effects were observed in combination group, while there was not response of mTOR to Aspp2-ad. In conclusion, Aspp2-ad, in P53-independent manner, regulated ERK and STAT3 signal moleculars to inhibit hepatocarcinoma in coordination with oxaliplatin by influencing the protein expression of proliferation, apoptosis, autophagy and vascular growth. Aspp2-ad has the potential to be developed in gene therapy for HCC, especially for P53 deletion or mutation in HCC.
Kas SM, de Ruiter JR, Schipper K, et al.Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma.
Nat Genet. 2017; 49(8):1219-1230 [PubMed
] Related Publications
Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype and accounts for 8-14% of all cases. Although the majority of human ILCs are characterized by the functional loss of E-cadherin (encoded by CDH1), inactivation of Cdh1 does not predispose mice to develop mammary tumors, implying that mutations in additional genes are required for ILC formation in mice. To identify these genes, we performed an insertional mutagenesis screen using the Sleeping Beauty transposon system in mice with mammary-specific inactivation of Cdh1. These mice developed multiple independent mammary tumors of which the majority resembled human ILC in terms of morphology and gene expression. Recurrent and mutually exclusive transposon insertions were identified in Myh9, Ppp1r12a, Ppp1r12b and Trp53bp2, whose products have been implicated in the regulation of the actin cytoskeleton. Notably, MYH9, PPP1R12B and TP53BP2 were also frequently aberrated in human ILC, highlighting these genes as drivers of a novel oncogenic pathway underlying ILC development.
Liu K, Lin D, Ouyang Y, et al.Amphiregulin impairs apoptosis-stimulating protein 2 of p53 overexpression-induced apoptosis in hepatoma cells.
Tumour Biol. 2017; 39(3):1010428317695026 [PubMed
] Related Publications
Overexpression of apoptosis-stimulating protein 2 of p53 (ASPP2) induces apoptotic cell death in hepatoma cells (e.g. HepG2 cells) by enhancing the transactivation activity of p53, but long-term ASPP2 overexpression fails to induce more apoptosis since activation of the epidermal growth factor/epidermal growth factor receptor/SOS1 pathway impairs the pro-apoptotic role of ASPP2. In this study, in recombinant adenovirus-ASPP2-infected HepG2 cells, ASPP2 overexpression induces amphiregulin expression in a p53-dependent manner. Although amphiregulin initially contributes to ASPP2-induced apoptosis, it eventually impairs the pro-apoptotic function of ASPP2 by activating the epidermal growth factor/epidermal growth factor receptor/SOS1 pathway, leading to apoptosis resistance. Moreover, blocking soluble amphiregulin with a neutralizing antibody also significantly increased apoptotic cell death of HepG2 cells due to treatment with methyl methanesulfonate, cisplatin, or a recombinant p53 adenovirus, suggesting that the function of amphiregulin involved in inhibiting apoptosis may be a common mechanism by which hepatoma cells escape from stimulus-induced apoptosis. Thus, our data elucidate an apoptosis-evasion mechanism in hepatocellular carcinoma and have potential implications for hepatocellular carcinoma therapy.
Fagerholm R, Khan S, Schmidt MK, et al.TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.
Oncotarget. 2017; 8(11):18381-18398 [PubMed
] Free Access to Full Article Related Publications
TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.
ASPP2 is a tumor suppressor that works, at least in part, through enhancing p53-dependent apoptosis. We now describe a new ASPP2 isoform, ΔN-ASPP2, generated from an internal transcription start site that encodes an N-terminally truncated protein missing a predicted 254 amino acids. ΔN-ASPP2 suppresses p53 target gene transactivation, promoter occupancy, and endogenous p53 target gene expression in response to DNA damage. Moreover, ΔN-ASPP2 promotes progression through the cell cycle, as well as resistance to genotoxic stress-induced growth inhibition and apoptosis. Additionally, we found that ΔN-ASPP2 expression is increased in human breast tumors as compared to adjacent normal breast tissue; in contrast, ASPP2 is suppressed in the majority of these breast tumors. Together, our results provide insight into how this new ASPP2 isoform may play a role in regulating the ASPP2-p53 axis.
Autophagy is an important catabolic process, which sustains intracellular homeostasis and lengthens cell survival under stress. Here we identify the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich region-containing protein 2 (ASPP2), a haploinsufficient tumor suppressor, as a molecular regulator of starvation-induced autophagy in hepatocellular carcinoma (HCC). ASPP2 expression is associated with an autophagic response upon nutrient deprivation and downregulation of ASPP2 facilitates autophagic flux, whereas overexpression of ASPP2 blocks this starvation-induced autophagy in HCC cells. Mechanistically, ASPP2 inhibits autophagy through regulating BECN1 transcription and formation of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) complex. Firstly, ASPP2 inhibits p65/RelA-induced transcription of BECN1, directly by an ASPP2-p65/RelA-IκBα complex which inhibits phosphorylation of IκBα and the translocation of p65/RelA into the nucleus. Secondly, ASPP2 binds to BECN1, leading to decreased binding of PIK3C3 and UV radiation resistance-associated gene (UVRAG), and increased binding of Rubicon in PIK3C3 complex. Downregulation of ASPP2 enhances the pro-survival and chemoresistant property via autophagy in HCC cells in vitro and in vivo. Decreased ASPP2 expression was associated with increased BECN1 and poor survival in HCC patients. Therefore, ASPP2 is a key regulator of BECN1-dependent autophagy, and decreased ASPP2 may contribute to tumor progression and chemoresistance via promoting autophagy.
Zick A, Kadouri L, Cohen S, et al.Recurrent TP53 missense mutation in cancer patients of Arab descent.
Fam Cancer. 2017; 16(2):295-301 [PubMed
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Hereditary cancer comprises more than 10% of all breast cancer cases. Identification of germinal mutations enables the initiation of a preventive program that can include early detection or preventive treatment and may also have a major impact on cancer therapy. Several recurrent mutations were identified in the BRCA1/2 genes in Jewish populations however, in other ethnic groups in Israel, no recurrent mutations were identified to date. Our group established panel sequencing in cancer patients to identify recurrent, founder, and new mutations in the heterogeneous and diverse populations in Israel, We evaluated five breast cancer patients of Arab descent diagnosed with cancer before the age of 50 years and identified the previously described TP53 mutation, c.541C>T, R181C (rs587782596), in two women from unrelated Arab families. The two probands were diagnosed with breast cancer at a young age (27 and 34 years) and had significant family history spanning a wide range of tumors (breast cancer (BC), papillary thyroid cancer, glioblastoma multiform (GBM), colon cancer and leukemia). The R181C variant is expected to disrupt p53 at the ASPP2 binding domain but not the DNA binding domain and is defined by Clinvar as likely pathogenic and in HGMD as disease mutation. We further tested 85 unrelated Arab cancer patients and father of a BC carrier patient for TP53 c.541C>T using a real time polymerase chain reaction (RT-PCR) approach and identified four additional carriers, two with BC one with lung cancer, and the father of a BC carrier patient, diagnosed with GBM. Another carrier suffering from BC was identified using a Myriad panel, suggesting a recurrent mutation in this population with a frequency of 5/42 (11.9%) of our selected BC patients. We suggest testing Arab women with a breast cancer at a young age, Arab patients with multiple malignancies, or with suggestive family history for TP53 c.541C>T.
Xu L, Tong X, Zhang S, et al.ASPP2 suppresses stem cell-like characteristics and chemoresistance by inhibiting the Src/FAK/Snail axis in hepatocellular carcinoma.
Tumour Biol. 2016; 37(10):13669-13677 [PubMed
] Related Publications
Hepatocellular carcinoma (HCC) is the third leading cause of death in cancer patients worldwide. Understanding the molecular pathogenesis of HCC recurrence and chemoresistance is key to improving patients' prognosis. In this study, we report that downregulation of ASPP2, a member of the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region-containing protein (ASPP) family, bestowed HCC cells with stem-like properties and resistance to chemotherapy, including the expansion of side population fractions, formation of hepatospheroids, expression of stem cell-associated genes, loss of chemosensitivity, and increased tumorigenicity in immunodeficient mice. An expression profiling assay revealed that ASPP2 specifically repressed focal adhesion kinase (FAK)/Src/extracellular signal regulated kinase (ERK) signaling. ASPP2 does this by physically interacting with C-terminal Src kinase (CSK) and stimulating its kinase activity, which eventually leads to activator protein 1 (AP1)-mediated downregulation of Snail expression. In addition, pharmacologic inhibition of Src attenuated the effects of ASPP2 deficiency. Our findings present functional and mechanistic insight into the critical role of ASPP2 in the inhibition of HCC stemness and drug resistance and may provide a new strategy for therapeutic combinations to treat HCC.
Ras-induced senescence mediated through ASPP2 represents a barrier to tumour formation. It is initiated by ASPP2's interaction with Ras at the plasma membrane, which stimulates the Raf/MEK/ERK signaling cascade. Ras to Raf signalling requires Ras to be organized in nanoscale signalling complexes, called nanocluster. We therefore wanted to investigate whether ASPP2 affects Ras nanoclustering. Here we show that ASPP2 increases the nanoscale clustering of all oncogenic Ras isoforms, H-ras, K-ras and N-ras. Structure-function analysis with ASPP2 truncation mutants suggests that the nanocluster scaffolding activity of ASPP2 converges on its α-helical domain. While ASPP2 increased effector recruitment and stimulated ERK and AKT phosphorylation, it did not increase colony formation of RasG12V transformed NIH/3T3 cells. By contrast, ASPP2 was able to suppress the transformation enhancing ability of the nanocluster scaffold Gal-1, by competing with the specific effect of Gal-1 on H-rasG12V- and K-rasG12V-nanoclustering, thus imposing ASPP2's ERK and AKT signalling signature. Similarly, ASPP2 robustly induced senescence and strongly abrogated mammosphere formation irrespective of whether it was expressed alone or together with Gal-1, which by itself showed the opposite effect in Ras wt or H-ras mutant breast cancer cells. Our results suggest that Gal-1 and ASPP2 functionally compete in nanocluster for active Ras on the plasma membrane. ASPP2 dominates the biological outcome, thus switching from a Gal-1 supported growth-promoting setting to a senescence inducing and stemness suppressive program in cancer cells. Our results support Ras nanocluster as major integrators of tumour fate decision events.
Liu H, Chen F, Zhang L, et al.A novel all-trans retinoic acid derivative 4-amino‑2‑trifluoromethyl-phenyl retinate inhibits the proliferation of human hepatocellular carcinoma HepG2 cells by inducing G0/G1 cell cycle arrest and apoptosis via upregulation of p53 and ASPP1 and downregulation of iASPP.
Oncol Rep. 2016; 36(1):333-41 [PubMed
] Related Publications
4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative, was reported to function as a tumor inhibitor in various types of cancer cells in vitro. However, little is known concerning its antitumor effect on human hepatocellular carcinoma (HCC) HepG2 cells. The aims of the present study were to investigate the effects of ATPR on the proliferation of HepG2 cells and to explore the probable mechanisms. A series of experiments were performed following the treatment of HepG2 cells with ATRA and ATPR. MTT and plate colony formation assays were used to measure the cell viability. To confirm the influence on proliferation, flow cytometry was used to detect the distribution of the cell cycle. Apoptosis was observed by Hoechst staining and flow cytometry. In addition, to characterize the underlying molecular mechanisms, immunofluorescence was applied to observe the distribution of p53. The transcription and translation levels of p53 were analyzed by real-time quantitative RT-PCR (qRT-PCR) and western blotting. The expression levels of murine double minute 2 (MDM2), apoptosis stimulating proteins of p53 (ASPP), cell cycle- and apoptosis-associated proteins were detected by western blotting. After HepG2 cells were incubated with ATRA and ATPR, the viability of the HepG2 cells was inhibited in a dose- and time-dependent manner. As well, ATPR significantly suppressed HepG2 cell colony formation and arrested cells at the G0/G1 phase, while ATRA had no obvious effects. Both Hoechst staining and flow cytometry unveiled the apoptosis of HepG2 cells. Moreover, the fluorescent density of p53 was higher in the nuclei after exposure to ATPR than that in the ATRA group. HepG2 cells treated with ATPR showed elevated mRNA and protein levels of p53 when compared with these levels in the ATRA-treated cells. Western blotting showed that ATPR increased ASPP1, p21 and Bax expression and decreased MDM2, iASPP, cyclin D and E, cyclin-dependent kinase 6 (CDK6) and Bcl-2 expression, while CDK4 and ASPP2 expression were scarcely altered. Consequently, ATPR exerted a better inhibitory effect on the proliferation of HepG2 cells than ATRA through increased expression of p53 and ASPP1 and downregulation of iASPP, thereby resulting in G0/G1 cell cycle arrest and apoptosis.
Suicide gene therapy using herpes simplex virus-1 thymidine kinase (HSV-TK) in combination with ganciclovir (GCV) has emerged as a potential new method for treating cancer. We hypothesize that the efficacy of HSV-TK/GCV therapy is at least partially dependent on p53 status in hepatocellular carcinoma (HCC) patients. Using recombinant adenoviral vectors (rAdV), TK, p53, and ASPP2 were overexpressed individually and in combination in Hep3B (p53 null) and HepG2 (p53 wild-type) cell lines and in primary HCC tumor cells. p53 overexpression induced death in Hep3B cells, but not HepG2 cells. ASPP2 overexpression increased rAdV-TK/GCV-induced HepG2 cell death by interacting with endogenous p53. Similarly, ASPP2 reduced survival in rAdV-TK/GCV-treated primary HCC cells expressing p53 wild-type but not a p53 R249S mutant. Mutated p53 was unable to bind to ASPP2, suggesting that the increase in rAdV-TK/GCV-induced cell death resulting from ASPP2 overexpression was dependent on its interaction with p53. Additionally, γ-H2AX foci, ATM phosphorylation, Bax, and p21 expression increased in rAdV-TK/GCV-treated HepG2 cells as compared to Hep3B cells. This suggests that the combined use of HSV-TK, GCV, rAdV-p53 and rAdV-ASPP2 may improve therapeutic efficacy in HCC patients lacking functional p53.
Fast growth and hardly any apoptosis are important characteristics of breast cancer, which assure the spread via invasion and metastasis of breast cancer cells. Inhibition of fast proliferation and induction of apoptosis are critical way to cure this cancer. microRNAs (miRNAs) had been increasingly reported to be the critical regulator of tumorigenesis. In our study, we found that increasing copy number of miR-548d-2-3p is critically involved poor prognosis. We overexpressed miR-548d-3p in MDA-MB-231cells and found that the proliferation was promoted significantly, whereas the inhibition of miR-548d-3p repressed the proliferation of MDA-MB-231 cells and also induced the increase in apoptosis. Additionally, we found that miR-548d-3p downregulated the expression of TP53BP2 by directly targeting the 3'UTR. We also found that knockdown of TP53BP2 significantly resorted the proliferation and apoptosis regulated by miR-548d-3p inhibitor. Our study showed that miR-548d-3p/TP53BP2 pathway is critically involved in the proliferation and apoptosis of breast cancer cells and may be new therapeutic target of breast cancer cells.
Li Y, Ahmad A, Sarkar FHASPP and iASPP: Implication in cancer development and progression.
Cell Mol Biol (Noisy-le-grand). 2015; 61(6):2-8 [PubMed
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The well-known guardian of genome, p53 plays critical roles in the induction of apoptosis typically upon DNA damage whereas mutant p53 containing cells are unable to undergo apoptosis which leads to aggressive tumor growth and drug resistance. Moreover, another molecule regulating wild-ype p53 function is ASPP (apoptosis stimulating proteins of p53) family. ASPP family consists of ASPP1 and ASPP2, and functions as tumor suppressors whereas the inhibitor of ASPP (iASPP) functions as oncogene. By binding to apoptosis regulating proteins such as p53, p63, p73, Bcl-2, NF-κB p65, etc., ASPP1 and ASPP2 promote apoptosis while overexpression of iASPP inhibits apoptotic cell death typically after DNA damage. In cancer cells, the aberrant expressions of ASPP1, ASPP2 and iASPP have been observed, especially, the high expression of iASPP in cancers is associated with worse disease status, therapy resistance and poor survival of patients with cancers. The molecular interactions between the members of ASPP family and their binding proteins in apoptotic pathway together with other regulators such as miR-124, NF-κB regulated Twist, snail, etc. form a complex signal transduction network to control apoptosis and tumor growth. Therefore, targeting ASPP family could regulate the aberrant communications in the signal transduction network to induce apoptosis and drug sensitivity. Several peptides, miRNAs and natural agents have been used to target ASPP family and show encouraging results in the induction of apoptosis of cancer cells; however, more in vivo animal studies and clinical trials are needed to confirm the true value of targeting ASPP family in the treatment of cancers.
Avilés-Jiménez F, Guitron A, Segura-López F, et al.Microbiota studies in the bile duct strongly suggest a role for Helicobacter pylori in extrahepatic cholangiocarcinoma.
Clin Microbiol Infect. 2016; 22(2):178.e11-178.e22 [PubMed
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Biliary tract cancer or extrahepatic cholangiocarcinoma (ECCA) represents the sixth commonest cause of cancer in the gastrointestinal tract in western countries. We aimed to characterize the microbiota and its predicted associated functions in the biliary tract of ECCA and benign biliary pathology (BBP). Samples were taken from 100 patients with ECCA and 100 patients with BBP by endoscopic cholangio-pancreatography for DNA extraction. Ten patients with ECCA and ten with BBP were selected for microbiota studies using the V4-16S rRNA gene and sequenced in Illumina platform. Microbiota analyses included sample-to-sample distance metrics, ordination/clustering and prediction of functions. Presence of Nesterenkonia sp. and Helicobacter pylori cagA and vacA genes were tested in the 100 ECCA and 100 BBP samples. Phylum Proteobacteria dominated all samples (60.4% average). Ordination multicomponent analyses showed significant microbiota separation between ECCA and BBP (p 0.010). Analyses of 4002 operational taxonomic units with presence variation in at least one category probed a separation of ECCA from BBP. Among these, Nesterenkonia decreased, whereas Methylophilaceae, Fusobacterium, Prevotella, Actinomyces, Novosphingobium and H. pylori increased in ECCA. Predicted associated functions showed increased abundance of H. pylori virulence genes in ECCA. cagA and vacA genes were confirmed by PCR in ECCA and BBP samples. This is the first microbiota report in ECCA and BBP to show significant changes in microbial composition. Bacterial species unusual for human flora were found: Methylophilaceae and Nesterenkonia are reported in hypersaline soils, and Mesorhizobium is a nitrogen-fixing bacterium. Enrichment of virulence genes confirms previous studies suggesting that H. pylori might be associated with ECCA.
BACKGROUND: Apoptosis-stimulating of p53 protein 2 (ASPP2) is one of the ASPP family members and it has been reported to be associated with human cancer. However, the role of it in pancreatic cancer is still not clear.
METHODS: We analyzed the expression level of ASPP2 in cancer tissue samples with RT-qPCR, Western Blotting assay and immunohistochemistry staining. We studied the biological function of ASPP2 and its mechanism with gene overexpression and gene silencing technologies. We determined the sensitivity of pancreatic cells with differential ASPP2 level to gemcitabine and whether autophagy inhibition affected the gemcitabine resistance, both in vitro and in vivo.
RESULTS: Expression of ASPP2 was downregulated in cancerous tissues in comparison with para-cancerous tissues. ASPP2 expression was linked to clinical outcomes in patients and down-regulation of ASPP2 increased cell proliferation, autophagic flux, the activity of AMP Kinase of pancreatic cancer cells and vice versa. Knockdown of ASPP2 results in increased resistance to gemcitabine, which was attributed to the enhanced autophagy.
CONCLUSIONS: ASSP2 expression is lower in cancerous tissues and decreased ASPP2 lead to higher cancer cells proliferation and autophagic flux, which contribute to the gemcitabine resistance.
INTRODUCTION: In triple negative breast cancers (TNBC) the initial response to chemotherapy is often favorable, but relapse and chemotherapy resistance frequently occur in advanced disease. Hence there is an urgent need for targeted treatments in this breast cancer subtype. In the current study we deep sequenced DNA of tumors prior to chemotherapy to search for predictors of response or resistance.
METHODS: Next generation sequencing (NGS) was performed for 1,977 genes involved in tumorigenesis. DNA from 56 pre-treatment TNBC-biopsies was sequenced, as well as matched normal DNA. Following their tumor biopsy, patients started neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. We studied associations between genetic alterations and three clinical variables: chemotherapy response, relapse-free survival and BRCA proficiency.
RESULTS: The mutations observed were diverse and few recurrent mutations were detected. Most mutations were in TP53, TTN, and PIK3CA (55 %, 14 %, and 9 %, respectively). The mutation rates were similar between responders and non-responders (average mutation rate 9 vs 8 mutations). No recurrent mutations were associated with chemotherapy response or relapse. Interestingly, PIK3CA mutations were exclusively observed in patients proficient for BRCA1. Samples with a relapse had a higher copy number alteration rate, and amplifications of TTK and TP53BP2 were associated with a poor chemotherapy response.
CONCLUSIONS: In this homogenous cohort of TNBCs few recurrent mutations were found. However, PIK3CA mutations were associated with BRCA proficiency, which can have clinical consequences in the near future.
ASPP2 can bind to p53 and enhance the apoptotic capabilities of p53 by guiding it to the promoters of pro-apoptotic genes. Here, ASPP2 overexpression for 24 hours transiently induced apoptosis in hepatoma cells by enhancing the transactivation of p53 on pro-apoptotic gene promoters. However, long-term ASPP2 overexpression (more than 48 hours) failed to induce apoptosis because p53 was released from the pro-apoptotic gene promoters. In non-apoptotic cells, nuclear EGFR induced SOS1 expression by directly binding to the SOS1 promoter. SOS1 activated the HRAS/PI3K/AKT pathway and resulted in nuclear translocation of p-AKT and Bcl-2. The interaction between p-AKT and ASPP2 facilitates Bcl-2 binding to p53, which releases p53 from the pro-apoptotic gene promoters. The in vivo assay demonstrated that EGFR/SOS1-promoted growth of nuclear p-AKT+, Bcl-2+ cells results in the resistance of hepatoma cells to ASPP2-p53 complex-induced apoptosis and that blocking nuclear translocation of EGFR dramatically improves and enhances the pro-apoptotic function of ASPP2. Finally, the activation of the HRAS/PI3K/AKT pathway by EGFR-induced SOS1 also inhibits cisplatin-induced apoptosis, suggesting a common apoptosis-evasion mechanism in hepatoma cells. Because evasion of apoptosis contributes to treatment resistance in hepatoma, our results also support further investigation of combined therapeutic blockade of EGFR and SOS1.
Romo-González T, Esquivel-Velázquez M, Ostoa-Saloma P, et al.The network of antigen-antibody reactions in adult women with breast cancer or benign breast pathology or without breast pathology.
PLoS One. 2015; 10(3):e0119014 [PubMed
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The Immunoglobulin G (IgG) antibody response to different protein antigens of the mammary ductal carcinoma by adult women affected by Breast Cancer (BC) distinguishes at least 103 proteins that differ in their molecular weights (MW). The IgG producing cell clones (nodes) coexist with each other in each individual organism and share energy resources among themselves, as well as factors that control the level of expression and Specificity of their IgG antibodies. So, it can be proposed that among them there is a Network of interconnections (links) unveiled by the antigens, which specifically react with the IgG antibodies produced by the clones. This Network possibly regulates IgG antibodies' activity and effectiveness. We describe the Network of nodes and links that exists between the different antigens and their respective IgG producing cell clones against the extracted protein antigens from the cells of the T47D Cell-Line, in 50 women with BC, 50 women with Benign Breast Pathology (BBP) and 50 women without breast pathology (H). We have found that women with BBP have the highest number of Links, followed by the H group and, lastly, the women with BC, a finding which suggests that cancer interferes with the Connectivity between the IgG producing cell clones and blocks the expression of 322 links in women with BBP and 32 links in women with H. It is also plausible that the largest number of links in the women with BBP indicates the Network's state of arousal that provides protection against BC. On the other hand, there were many missing links in the BC group of women; the clone which lost more links in the BC group was the hub 24, which point to some of the antigens of T47D as potentially useful as vaccines, as the immune system of women with BBP is well aware of them.
Wang Y, Bu F, Royer C, et al.ASPP2 controls epithelial plasticity and inhibits metastasis through β-catenin-dependent regulation of ZEB1.
Nat Cell Biol. 2014; 16(11):1092-104 [PubMed
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Epithelial to mesenchymal transition (EMT), and the reverse mesenchymal to epithelial transition (MET), are known examples of epithelial plasticity that are important in kidney development and cancer metastasis. Here we identify ASPP2, a haploinsufficient tumour suppressor, p53 activator and PAR3 binding partner, as a molecular switch of MET and EMT. ASPP2 contributes to MET in mouse kidney in vivo. Mechanistically, ASPP2 induces MET through its PAR3-binding amino-terminus, independently of p53 binding. ASPP2 prevents β-catenin from transactivating ZEB1, directly by forming an ASPP2-β-catenin-E-cadherin ternary complex and indirectly by inhibiting β-catenin's N-terminal phosphorylation to stabilize the β-catenin-E-cadherin complex. ASPP2 limits the pro-invasive property of oncogenic RAS and inhibits tumour metastasis in vivo. Reduced ASPP2 expression results in EMT, and is associated with poor survival in hepatocellular carcinoma and breast cancer patients. Hence, ASPP2 is a key regulator of epithelial plasticity that connects cell polarity to the suppression of WNT signalling, EMT and tumour metastasis.
Apoptosis-stimulating protein of p53-2 (ASPP2) induces apoptosis by promoting the expression of pro-apoptotic genes via binding to p53 or p73; however, the exact mechanisms by which ASPP2 induces apoptotic death in hepatoma cells are still unclear. Here, we show that the transient overexpression of ASPP2 induces autophagic apoptosis in hepatoma cells by promoting p53- or p73-independent C/EBP homologous protein (CHOP) expression. CHOP expression decreases the expression of Bcl-2; this change releases Beclin-1 from cytoplasmic Bcl-2-Beclin-1 complexes and allows it to initiate autophagy. However, transient overexpression of Beclin-1 can induce autophagy but not apoptosis. Our results show that ASPP2 induces the expression of damage-regulated autophagy modulator (DRAM), another critical factor that cooperates with free Beclin-1 to induce autophagic apoptosis. The effect of CHOP on the translocation and sequestration of Bcl-2 in the nucleus, which requires the binding of Bcl-2 to ASPP2, is also critical for ASPP2-induced autophagic apoptosis. Although the role of nuclear ASPP2-Bcl-2 complexes is still unclear, our results suggest that nuclear ASPP2 can prevent the translocation of the remaining Bcl-2 to the cytoplasm by binding to Bcl-2 in a CHOP-dependent manner, and this effect also contributes to Beclin-1-initiated autophagy. Thus, CHOP is critical for mediating ASPP2-induced autophagic apoptosis by decreasing Bcl-2 expression and maintaining nuclear ASPP2-Bcl-2 complexes. Our results, which define a mechanism whereby ASPP2 overexpression induces autophagic apoptosis, open a new avenue for promoting autophagy in treatments to cure hepatocellular carcinoma.
Inflammation and loss of cell polarity play pivotal roles in neurodegeneration and cancer. A central question in both diseases is how the loss of cell polarity is sensed by cell death machinery. Here, we identify apoptosis-stimulating protein of p53 with signature sequences of ankyrin repeat-, SH3 domain-, and proline-rich region-containing protein 2 (ASPP2), a haploinsufficient tumor suppressor, activator of p53, and regulator of cell polarity, as a transcriptional target of signal transducer and activator of transcription 1 (STAT1). LPS induces ASPP2 expression in murine macrophage and microglial cell lines, a human monocyte cell line, and primary human astrocytes in vitro. LPS and IFNs induce ASPP2 transcription through an NF-κB RELA/p65-independent but STAT1-dependent pathway. In an LPS-induced maternal inflammation mouse model, LPS induces nuclear ASPP2 in vivo at the blood-cerebral spinal fluid barrier (the brain's barrier to inflammation), and ASPP2 mediates LPS-induced apoptosis. Consistent with the role of ASPP2 as a gatekeeper to inflammation, ASPP2-deficient brains possess enhanced neuroinflammation. Elevated ASPP2 expression is also observed in mouse models and human neuroinflammatory disease tissue, where ASPP2 was detected in GFAP-expressing reactive astrocytes that coexpress STAT1. Because the ability of ASPP2 to maintain cellular polarity is vital to CNS development, our findings suggest that the identified STAT1/ASPP2 pathway may connect tumor suppression and cell polarity to neuroinflammation.
Increased expression of angiotensin II type 2 receptor (AT2R) induces apoptosis in numerous tumor cell lines, with either Angiotensin II-dependent or Angiotensin II-independent regulation, but its molecular mechanism remains poorly understood. Here, we used PCR Array analysis to determine the gene and microRNA expression profiles in human prostate cancer cell lines transduced with AT2R recombinant adenovirus. Our results demonstrated that AT2R over expression leads to up-regulation of 6 apoptosis-related genes (TRAIL-R2, BAG3, BNIPI, HRK, Gadd45a, TP53BP2), 2 cytokine genes (IL6 and IL8) and 1 microRNA, and down-regulation of 1 apoptosis-related gene TNFSF10 and 2 cytokine genes (BMP6, BMP7) in transduced DU145 cells. HRK was identified as an up-regulated gene in AT2R-transduced PC-3 cells by real-time RT-PCR. Next, we utilized siRNAs to silence the up-regulated genes to further determine their roles on AT2R overexpression mediated apoptosis. The results showed downregulation of Gadd45a reduced the apoptotic effect by ∼30% in DU145 cells, downregulation of HRK reduced AT2R-mediated apoptosis by more than 50% in PC-3 cells, while downregulation of TRAIL-R2 enhanced AT2R-mediated apoptosis more than 4 times in DU145 cells. We also found that the effects on AT2R-mediated apoptosis caused by downregulation of Gadd45a, TRAIL-R2 and HRK were independent in activation of p38 MAPK, p44/42 MAPK and p53. Taken together, our results demonstrated that TRAIL-R2, Gadd45a and HRK may be novel target genes for further study of the mechanism of AT2R-mediated apoptosis in prostate cancer cells.