Research IndicatorsGraph generated 29 August 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 29 August, 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: TRPM2 (cancer-related)
Yalçın E, Pala Ş, Atılgan R, et al.Is there any difference between endometrial hyperplasia and endometrial carcinoma in terms of expression of TRPM2 and TRPM7 ion channels?
Turk J Med Sci. 2019; 49(2):653-660 [PubMed
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Background/aim: This study compared TRPM2 and TRPM7 ion channel gene expression and immunohistochemical staining in endometrial hyperplasia and endometrium adenocarcinoma.
Materials and methods: Sections were taken from paraffin blocks of 120 patients who were divided into 6 groups as follows: G1 (n = 20), proliferative endometrium (PE); G2 (n = 20), EH without atypia; G3 (n = 20), EH with atypia; G4 (n = 20), stage 1A, grade 1 EC; G5 (n = 20), stage 1A, grade 2 EC; and G6 (n = 20), stage 1A, grade 3 EC. TRPM2 and TRPM7 genes were analyzed with qRT-PCR in paraffin-embedded tissue samples. Under light microscopy, TRPM2 and TRPM7 immunostaining scores of the samples taken from polylysine slides were evaluated.
Results: Compared to G1, TRPM2 mRNA gene expression was significantly downregulated in G3 and G5. TRPM2 immunoreactivity scores were similar in all groups. TRPM7 mRNA gene expression was significantly downregulated in G2, G3, and G6 when compared to G1. TRPM7 immunoreactivity scores were similar in G1, G2, and G3, but significantly decreased in G4, G5, and G6
Conclusion: Reduction in TRPM7 ion channel activity may be a progression marker for endometrial hyperplasia regardless of the atypical criteria.
Tektemur A, Ozaydin S, Etem Onalan E, et al.TRPM2 mediates distruption of autophagy machinery and correlates with the grade level in prostate cancer.
J Cancer Res Clin Oncol. 2019; 145(5):1297-1311 [PubMed
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PURPOSE: Transient receptor potential melastatin 2 (TRPM2), a calcium-permeable ion channel, is shown as a prognostic marker candidate in prostate cancer (PCa) and an important regulator of autophagy. We aimed to determine the changes in TRPM2 and autophagic-apoptotic gene expression levels in human prostate adenocarcinomas, and to investigate the affect of TRPM2 on autophagic pathways in PC-3 cell line.
METHODS: Human prostate tissues were classified considering the grade levels and were divided into the control, BPH, and grade 1-5 groups. mRNA expression levels of genes were determined by qPCR. In addition, TRPM2 was evaluated immunohistochemically for each group. In PC-3 cell line, TRPM2 was silenced through siRNA transfection, and autophagy induction was analyzed by acridine orange (AO) staining.
RESULTS: The qPCR and immunoreactivity results showed that the increased TRPM2 expression levels in human PCa samples were paralleled with higher grade levels. The autophagic-apoptotic gene expressions showed high variability in different grade levels. Also, silencing TRPM2 in PC-3 cells altered autophagic gene expressions and caused autophagy induction according to the AO staining results.
CONCLUSION: We showed that the autophagy-TRPM2 association may take place in the molecular basis of PCa and accordingly this connection may be targeted as a new therapeutic approach in PCa.
BACKGROUND: To date, the elucidation of serum protein alterations in male breast cancer (MBC) has not been extensively studied, due to the rarity of the disease.
MATERIALS AND METHODS: In the present work, two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) were employed to detect differences in serum protein expression between patients with MBC and healthy controls.
RESULTS: A panel of differentially expressed serum proteins was identified, including proteins involved in the regulation of the cell cycle [e.g. cell division cycle 7-related protein kinase (CDC7)], in mitochondrial function [e.g. mitochondrial aldehyde dehydrogenase (ALDH2) and dimethyladenosine transferase 1 (TFB1M)], in lipid metabolism and transport [e.g. apolipoprotein A-I (APOA1) and E (APOE)], in apoptosis and immune response [e.g. CD5 antigen-like (CD5L), clusterin (CLUS) and C-C motif chemokine 14 (CCL14)], in transcription (e.g. protein SSX3 and signal transducer and activator of transcription 3 (STAT3)], in invasion and metastasis (e.g. alpha-2-HS-glycoprotein (FETUA)], in estrogen synthesis [aromatase (CYP19A1)] and other diverse biological roles [e.g. actin-related protein 2/3 complex subunit 4 (ARPC4), dual specificity mitogen-activated protein kinase kinase 4 (MP2K4), ectoderm-neural cortex protein 1 (ENC1), and matrix metalloproteinase-27 (MMP27)].
CONCLUSION: These findings provide valuable insight into the distinct clinicopathological features of MBC and indicate that select serum proteomic markers may help improve MBC management.
Zhang L, Luo M, Yang H, et al.Next-generation sequencing-based genomic profiling analysis reveals novel mutations for clinical diagnosis in Chinese primary epithelial ovarian cancer patients.
J Ovarian Res. 2019; 12(1):19 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Ovarian cancer (OC) is one of the most malignant gynecological tumors, associated with excess death rate (50-60%) in ovarian cancer patients. Particularly, among newly occurred ovarian cancer patients, 70% of clinical cases are diagnosed at the advanced stage, which definitely delay the timely treatment and lead to high mortality rate within 5 years post diagnosis. Therefore, identification of sensitive gene markers, as well as development of reliable genetic diagnosis, are important for the early detection and precise therapy for OC patients. This study aims to identify novel genetic mutations and develop a feasible clinical approach for early OC diagnosis.
METHODS: The OC tissue-derived DNA sample was acquired from 31 OC patients, and the somatic gene mutations will be identified after comparison with normal samples, using Genome-wide analysis and next-generation sequencing.
RESULTS: A total of 463 somatic mutations, which were considered as potential pathogenic sites, were assigned to 473 genes. Among them, 15 genes (TP53, TTN, MUC16, OR4N2, BRCA1, CAD, CCDC129, INSR, NAV3, NELL2, NRAS, OBSCN, PGLYRP4, RBM15B and TRPC7) were mutated on at least two sites. These genes were mapped to RNA sequencing (RNAseq) data, and a total of 117 genes had an absolute fold- change ≥ 2 and p ≤ 0.01. Five genes were mutated in at least two OC patients. Gene ontology (GO) classification indicated that a majority of genes participated in biological processes. Kyoto Enrichment of Genes and Genomes (KEGG) enrichment pathway analysis revealed that the genes were mainly involved in the regulation of metabolic signaling pathways.
CONCLUSIONS: Taken together, this study identified several novel genetic alterations pathway for early clinical diagnosis and provided abundant information for understanding molecular mechanisms of the OC occurrence and development.
Bouaouiche S, Magadoux L, Dondaine L, et al.Glyceryl trinitrate‑induced cytotoxicity of docetaxel‑resistant prostatic cancer cells is associated with differential regulation of clusterin.
Int J Oncol. 2019; 54(4):1446-1456 [PubMed
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Metastatic castration resistant prostate cancer (mCRPC) relapse due to acquired resistance to chemotherapy, such as docetaxel, remains a major threat to patient survival. Resistance of mCRPC to docetaxel can be associated with elevated levels of soluble clusterin (sCLU) and growth differentiation factor‑15 (GDF‑15). Any strategies aiming to modulate sCLU and/or GDF‑15 in docetaxel‑resistant prostate cancer cells present a therapeutic interest. The present study reports the cytotoxic effect of a nitric oxide donor, glyceryl trinitrate (GTN), on docetaxel‑resistant mCRPC human cell lines and demonstrates that GTN displays greater inhibition of cell viability toward docetaxel‑resistant mCRPC cells than on mCRPC cells. It is also demonstrated that GTN modulates the level of expression of clusterin (CLU) which is dependent of GDF‑15, two markers associated with docetaxel resistance in prostate cancer. The results indicate that GTN represses the level of expression of the cytoprotective isoform of CLU (sCLU) and can increase the level of expression of the cytotoxic isoform (nuclear CLU) in docetaxel resistant cells. Furthermore, it was observed that GTN differentially regulates the level of the precursor form of GDF‑15 between resistant and parental cells, and that recombinant GDF‑15 can modulate the expression of CLU isoforms and counteract GTN‑induced cytotoxicity in resistant cells. A link was established between GDF‑15 and the expression of CLU isoforms. The present study thus revealed GTN as a potential therapeutic strategy to overcome docetaxel‑resistant mCRPC.
Shu F, Zou X, Tuo H, et al.Stathmin gene silencing suppresses proliferation, migration and invasion of gastric cancer cells via AKT/sCLU and STAT3 signaling.
Int J Oncol. 2019; 54(3):1086-1098 [PubMed
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Globally, gastric cancer is the fifth most common malignancy, with high rates of incidence and mortality. The high mortality rate and poor prognosis of gastric cancer are closely associated with its profound invasiveness, high incidence of metastasis, rapid proliferation, and high rate of recurrence. Previous studies have confirmed that stathmin (STMN) has an important role in the occurrence, development and prognosis of gastric cancer. However, the detailed mechanisms by which STMN affects these processes remain unclear. The aim of the present study was to determine how STMN promotes invasion, migration and proliferation in gastric cancer tumor cells. The results of immunohistochemistry indicated that STMN is overexpressed in stomach neoplasm tissues, and that it is associated with migration, invasion, proliferation and anti‑apoptotic states of gastric cancer cells. The secretory proteins of gastric cancer cells with or without STMN knockdown were further analyzed using the isobaric tags for relative and absolute quantitation method to identify differentially expressed proteins verified by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. Inhibition of STMN decreases the levels of clusterin, cystatin C and matrix metalloproteinases, followed by inhibiting the protein kinase B and signal transducer and activation of transcription activation. These findings suggest that STMN could be a promising therapeutic target for gastric cancer.
Modulation or prevention of protein changes during the cholangiocarcinoma (CCA) process induced by Opisthorchis viverrini (Ov) infection may become a key strategy for prevention and treatment of CCA. Monitoring of such changes could lead to discovery of protein targets for CCA treatment. Curcumin exerts anti-inflammatory and anti-CCA activities partly through its protein-modulatory ability. To support the potential use of curcumin and to discover novel target molecules for CCA treatment, we used a quantitative proteomic approach to investigate the effects of curcumin on protein changes in an Ov-induced CCA-harboring hamster model. Isobaric labelling and tandem mass spectrometry were used to compare the protein expression profiles of liver tissues from CCA hamsters with or without curcumin dietary supplementation. Among the dysregulated proteins, five were upregulated in liver tissues of CCA hamsters but markedly downregulated in the CCA hamsters supplemented with curcumin: S100A6, lumican, plastin-2, 14-3-3 zeta/delta and vimentin. Western blot and immunohistochemical analyses also showed similar expression patterns of these proteins in liver tissues of hamsters in the CCA and CCA + curcumin groups. Proteins such as clusterin and S100A10, involved in the NF-κB signaling pathway, an important signaling cascade involved in CCA genesis, were also upregulated in CCA hamsters and were then suppressed by curcumin treatment. Taken together, our results demonstrate the important changes in the proteome during the genesis of O. viverrini-induced CCA and provide an insight into the possible protein targets for prevention and treatment of this cancer.
Hirschler-Laszkiewicz I, Chen SJ, Bao L, et al.The human ion channel TRPM2 modulates neuroblastoma cell survival and mitochondrial function through Pyk2, CREB, and MCU activation.
Am J Physiol Cell Physiol. 2018; 315(4):C571-C586 [PubMed
] Free Access to Full Article Related Publications
Transient receptor potential melastatin channel subfamily member 2 (TRPM2) has an essential function in cell survival and is highly expressed in many cancers. Inhibition of TRPM2 in neuroblastoma by depletion with CRISPR technology or expression of dominant negative TRPM2-S has been shown to significantly reduce cell viability. Here, the role of proline-rich tyrosine kinase 2 (Pyk2) in TRPM2 modulation of neuroblastoma viability was explored. In TRPM2-depleted cells, phosphorylation and expression of Pyk2 and cAMP-responsive element-binding protein (CREB), a downstream target, were significantly reduced after application of the chemotherapeutic agent doxorubicin. Overexpression of wild-type Pyk2 rescued cell viability. Reduction of Pyk2 expression with shRNA decreased cell viability and CREB phosphorylation and expression, demonstrating Pyk2 modulates CREB activation. TRPM2 depletion impaired phosphorylation of Src, an activator of Pyk2, and this may be a mechanism to reduce Pyk2 phosphorylation. TRPM2 inhibition was previously demonstrated to decrease mitochondrial function. Here, CREB, Pyk2, and phosphorylated Src were reduced in mitochondria of TRPM2-depleted cells, consistent with their role in modulating expression and activation of mitochondrial proteins. Phosphorylated Src and phosphorylated and total CREB were reduced in TRPM2-depleted nuclei. Expression and function of mitochondrial calcium uniporter (MCU), a target of phosphorylated Pyk2 and CREB, were significantly reduced. Wild-type TRPM2 but not Ca
Ma X, Zou L, Li X, et al.MicroRNA-195 regulates docetaxel resistance by targeting clusterin in prostate cancer.
Biomed Pharmacother. 2018; 99:445-450 [PubMed
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MicroRNAs (miRNAs) have been implicated in neoplasm growth, metastasis, vasculogenesis, and drug resistance. It has been validated that abnormal miR-195 expression was related with poor survival of prostate cancer (PC); however, its role in the resistance to chemotherapeutic drugs docetaxel (DOC) in PC is still acquainted scarcely. In our study, the lower expression of miR-195 was appeared in DOC-resistant PC cells (DU145/DOC) rather than DOC-sensitive DU145 cells. The up-regulation of miR-195 lowered the IC50 of DOC, facilitated the apoptosis and inhibited the colony formation ability in DU145/DOC cells. Moreover, we also found that miR-195 had the binding site with clusterin (CLU) by the online TargetScan database mining. Luciferase tests revealed that miR-195 binds to the 3'-UTR of CLU. MiR-195 overexpression decreased the amassment of CLU in DU145/DOC cells. Knockdown of CLU diminished the IC50 of DOC and enhanced the apoptosis of DU145/DOC cells, which was consistent with the influence of miR-195 on DOC-induced cell apoptosis. Taken together, our results illuminated that miR-195 improved the sensitivity of resistant PC cells to DOC by suppressing CLU. Hence, miR-195 may be a potentially promising molecular target for drug resistance of PC.
The long non-coding RNA maternally expressed gene 3 (MEG3) is frequently dysregulated in human cancers; however, its roles in colorectal cancer (CRC) development are largely unknown. Here, we reported that MEG3 was down-regulated in CRC tissues and CRC patients with lower MEG3 showed poorer overall survival and disease-free survival than those with higher MEG3 level. MEG3 over-expression represses CRC cells proliferation and migration in vivo and in vitro, while MEG3 knockdown leads to the enhanced proliferation and metastasis of CRC cells. In CRC cells, MEG3 over-expression is related to decreased Clusterin mRNA and the corresponding protein levels, and it also directly binds to Clusterin protein through its 732-1174 region. In further, Clusterin over-expression rescues the compromised abilities of proliferation and metastasis induced by MEG3 over-expression, suggesting that MEG3 inhibits the CRC progression through regulating the Clusterin activities. Additionally, we found that 1α,25-(OH)
The aim of the present study was to investigate transient receptor potential cation channel subfamily M member 2 (TRPM2), a promising therapeutic target and biomarker for pancreatic ductal adenocarcinoma (PDAC) prognosis, in addition to determining its effects regarding tumor progression and invasion. PDAC is a fatal disease with a poor prognosis, and its associated pathogenic molecular mechanisms remain to be determined. In the present study, combined analysis using genomic and transcriptomic data from two PDAC studies was performed to discover a survival‑associated biomarker of PDAC. Survival analysis for genes mutated in ≥10 patients was performed using a Kaplan‑Meier curve and tested for significance using a log‑rank test. Furthermore, gene‑expression correlation analysis was performed to determine the genes with the strongest correlations to TRPM2. In addition, a Cell Counting Kit‑8 assay, a scratch wound‑healing assay and a Transwell assay were performed in the present study to investigate the proliferative, invasive and metastatic ability of PANC‑1 cells in TRPM2‑overexpressing and downregulated groups. The mutated TRPM2 gene had a strong negative correlation with patient survival probability compared with the normal control group (P=1.06x10‑4). Expression of TRPM2 was strongly correlated with expression of probable phospholipid‑transporting ATPase IM, γ‑parvin, tudor domain containing 9, Toll‑like receptor 7 and Scm‑like with four MBT domains protein 2 according to the criterion of a correlation coefficient >0.5. Furthermore, the results of the present study demonstrated that the TRPM2 overexpression in a PDAC cell line (PANC‑1) promoted cell proliferation, invasion and metastatic ability. TRPM2 represents a potential therapeutic target and prognostic marker for patients with PDAC. TRPM2 regulates cell proliferation, invasion and migration; however, the underlying mechanism requires further investigation in future studies.
Prostate cancer is a common cause of cancer-related death in men. E6AP (E6-Associated Protein), an E3 ubiquitin ligase and a transcription cofactor, is elevated in a subset of prostate cancer patients. Genetic manipulations of E6AP in prostate cancer cells expose a role of E6AP in promoting growth and survival of prostate cancer cells
Zhong J, Yu X, Dong X, et al.Downregulation of secreted clusterin potentiates the lethality of sorafenib in hepatocellular carcinoma in association with the inhibition of ERK1/2 signals.
Int J Mol Med. 2018; 41(5):2893-2900 [PubMed
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Secretory clusterin (sCLU) is overexpressed in cancer and is associated with resistance to chemotherapy in several types of cancer, including hepatocellular carcinoma (HCC). Sorafenib (SOR), a multikinase inhibitor of Raf/mitogen‑activated protein kinase kinase/extracellular signal‑regulated kinase (ERK) signaling and the receptor tyrosine kinase, is recognized as the standard therapeutic strategy for patients with advanced HCC. However, the role of sCLU in the resistance of HCC to SOR remains to be fully elucidated. In the present study, sCLU was silenced by CLU short hairpin (sh)RNA in Bel‑7402 and SMMC‑7721 cell lines, following which the cells were treated with SOR. Cell proliferation was determined using a CCK‑8 assay. Apoptosis was quantified using flow cytometry. The production of sCLU, B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X sprotein and phosphorylated (p)ERK1/2 was analyzed using western blot analysis. The results showed that sCLU was overexpressed in three HCC cell lines. The downregulation of sCLU by CLU shRNA synergistically increased SOR sensitivity in the Bel‑7402 and SMMC‑7721 cells, and potentiated SOR‑induced cell apoptosis. In addition, silencing sCLU or combination with PD98059 decreased the SOR‑induced activation of pERK1/2. These findings indicate a novel treatment strategy for HCC.
Liu Y, Men C, Xu Y, et al.Clusterin promotes growth and invasion of clear cell renal carcinoma cell by upregulation of S100A4 expression.
Cancer Biomark. 2018; 21(4):915-923 [PubMed
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BACKGROUND AND OBJECTIVE: Clusterin promotes cell proliferation, motility and invasiveness in human renal cell carcinoma (RCC) cells but the underlying molecular mechanisms of this action are largely unknown. The aim of this study was to investigate the effects of clusterin on cancer cell growth, invasion and S100A4 expression and to determine the effects of clusterin on in vitro cell proliferation and migration and in vivo tumour growth in RCC cells.
METHODS: We have established stable transfectants of highly invasive Caki-1 human RCC cells with expression of clusterin shRNA targeting clusterin (Caki-1/clusterin shRNA). We also established stable transfectants of 786-O human RCC cells with expression of clusterin cDNA plaismid (786-O/clusterin cDNA). Clusterin and S100A4 expression was detected by reverse transcription (RT) PCR and western blot assay; Caki-1/clusterin shRNA and 786-O/clusterin cDNA clones were subjected to in vitro-invasion assays. Cell viability and cell growth was assessed in MTT and clonogenic assay. Specific small interfering RNA was employed to down-regulate S100A4. The expression plasmid for S100A4 (pCMV-S100A4) was used to upregulate S100A4. Caki-1/clusterin shRNA clones were injected subcutaneously in nude mice to determine tumour growth and cancer cell invasiveness in vivo. Xenograft tumour tissues were assessed by immunohistochemistry and frozen tissues were used for the detection of S100A4 and clusterin.
RESULTS: Overexpression of clusterin increased cell invasiveness; and targeting clusterin reduced cell invasiveness in vitro. This increase in cell invasiveness was mediated by S100A4. Targeting clusterin decreased cell proliferation and down-regulated cellular S100A4 levels in Caki-1 cells; Overexpression of clusterin increased cell proliferation and up-regulated cellular S100A4 levels in 786-O cells; Stable Caki-1/clusterin shRNA transfectants produced smaller xenograft tumours containing reduced S100A4 protein levels in vivo. Stable 786-O/clusterin cDNA transfectants produced larger xenograft tumours containing increased S100A4 protein levels in vivo.
CONCLUSION: Our results indicate that clusterin promotes growth and invasion in RCC cells in vitro and in vivo through upregulation of S100A4; And targeting clusterin confers growth inhibitory and anti-invasive properties in RCC cells in vitro and in vivo through a down-regulation of S100A4. These findings provide the rationale for future oncostatic strategies aimed at suppressing clusterin-mediated signal transduction pathways as a novel therapeutic approach in human RCC.
Almasi S, Kennedy BE, El-Aghil M, et al.TRPM2 channel-mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway.
J Biol Chem. 2018; 293(10):3637-3650 [PubMed
] Free Access to Full Article Related Publications
A lack of effective treatment is one of the main factors contributing to gastric cancer-related death. Discovering effective targets and understanding their underlying anti-cancer mechanism are key to achieving the best response to treatment and to limiting side effects. Although recent studies have shown that the cation channel transient receptor potential melastatin-2 (TRPM2) is crucial for cancer cell survival, the exact mechanism remains unclear, limiting its therapeutic potential. Here, using molecular and functional assays, we investigated the role of TRPM2 in survival of gastric cancer cells. Our results indicated that TRPM2 knockdown in AGS and MKN-45 cells decreases cell proliferation and enhances apoptosis. We also observed that the TRPM2 knockdown impairs mitochondrial metabolism, indicated by a decrease in basal and maximal mitochondrial oxygen consumption rates and ATP production. These mitochondrial defects coincided with a decrease in autophagy and mitophagy, indicated by reduced levels of autophagy- and mitophagy-associated proteins (
Kim YS, Jin HO, Hong SE, et al.Silencing of secretory clusterin sensitizes NSCLC cells to V-ATPase inhibitors by downregulating survivin.
Biochem Biophys Res Commun. 2018; 495(2):2004-2009 [PubMed
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Secretory clusterin (sCLU) is a stress-associated protein that confers resistance to therapy when overexpressed. In this study, we observed that the V-ATPase inhibitors bafilomycin A1 and concanamycin A significantly stimulated sCLU protein expression. Knockdown of sCLU with siRNA sensitized non-small cell lung cancer (NSCLC) cells to bafilomycin A1, suggesting that sCLU expression renders cells resistant to V-ATPase inhibitors. The dual PI3K/AKT and mTOR inhibitor BEZ235 suppressed sCLU expression and enhanced cell sensitivity induced by bafilomycin A1. Notably, sCLU knockdown further decreased the expression of the survivin protein by bafilomycin A1, and the ectopic expression of survivin alleviated the cell sensitivity by bafilomycin A1 and sCLU depletion, suggesting that increased sensitivity to sCLU depletion in the cells with V-ATPase inhibitors is due, at least in part, to the down-regulation of survivin. Taken together, we demonstrated that the depletion of sCLU expression enhances the sensitivity of NSCLC cells to V-ATPase inhibitors by decreasing survivin expression. Inhibition of the PI3K/AKT/mTOR pathway enhances the sensitivity of NSCLC cells to V-ATPase inhibitors, leading to decreased sCLU and survivin expression. Thus, we suggest that a combination of PI3K/AKT/mTOR inhibitors with V-ATPase inhibitors might be an effective approach for NSCLC treatment.
Background: Deleted in Liver Cancer 1 (DLC1) is a tumor suppressor gene frequently deleted in cancer. However, DLC1 is not known to be deleted in angiosarcoma, an aggressive malignancy of endothelial cell derivation. Additionally, the physiologic functions of DLC1 protein in endothelial cells are poorly defined.
Methods: We investigated the effects of shRNA-induced DLC1 depletion in endothelial cells. Cell growth was measured by 3H thymidine incorporation, IncuCyte imaging, and population doublings; cell death by cell cycle analysis; gene expression by Affimetrix arrays and quantitative polymerase chain reaction; NF-κB activity by reporter assays; and protein levels by immunoblotting and immunofluorescence staining. We tested Tanespimycin/17-AAG and Fasudil treatment in groups of nine to 10 mice bearing ISOS-1 angiosarcoma. All statistical tests were two-sided.
Results: We discovered that DLC1 is a critical regulator of cell contact inhibition of proliferation in endothelial cells, promoting statistically significant (P < .001) cell death when cells are confluent (mean [SD] % viability: control DLC1 = 15.6 [19.3]; shDLC1 = 73.4 [13.1]). This prosurvival phenotype of DLC1-depleted confluent endothelial cells is attributable to a statistically significant and sustained increase of NF-κB activity (day 5, P = .001; day 8, P = .03) associated with increased tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) signaling. Consistently, we found that DLC1 is statistically significantly reduced (P < .001 in 5 of 6) and TNFAIP3/A20 is statistically significantly increased (P < .001 in 2 of 3 and P = 0.02 in 1 of 3) in human angiosarcoma compared with normal adjacent endothelium. Treatment with the NF-κB inhibitor Tanespimycin/17-AAG statistically significantly reduced angiosarcoma tumor growth in mice (treatment tumor weight vs control, 0.50 [0.19] g vs 0.91 [0.21] g, P = .001 experiment 1; 0.66 [0.26] g vs 1.10 [0.31] g, P = .01 experiment 2).
Conclusions: These results identify DLC1 as a previously unrecognized regulator of endothelial cell contact inhibition of proliferation that is depleted in angiosarcoma and support NF-κB targeting for the treatment of angiosarcoma where DLC1 is lost.
BACKGROUND: Secreted clusterin (sCLU), a 75-80 kDa disulfide-linked heterodimeric protein, plays crucial roles in various pathophysiological processes, including lipid transport, tissue remodeling, cell apoptosis and reproduction. Our previous studies demonstrated that sCLU could influence cell apoptosis, proliferation, and invasion of non-small cell lung cancer (NSCLC) cells.
METHODS: In this study, clusterin's function in regulating transdifferentiation of NSCLC cells was investigated. In addition, we examined the correlation between clusterin and clinicopathological features of lung cancer.
RESULTS: We found that clusterin was increased in lung adenocarcinoma tissues and decreased in lung squamous cell carcinoma tissues through immunohistochemical technique. In cultured lung adenocarcinoma cell lines, clusterin addition could increase SP-C protein expression in 2.75-fold, and decrease p63 protein expression in 0.65-fold (1.54 to 1). And also clusterin addition could increase SP-C mRNA expression in 4.05-fold, decreased p63 mRNA expression in 0.51-fold.
CONCLUSIONS: Our study demonstrated that clusterin could promote EMT and influence transdifferentiation from lung squamous cell carcinoma to lung adenocarcinoma. However, we found that clusterin expression have no correlation with malignance associate clinicopathological data. Our study may help to further elucidate the development and progression of NSCLC, also it may contribute to the research of therapies targeting sCLU.
Garcia-Aranda M, Serrano A, Redondo MRegulation of Clusterin Gene Expression.
Curr Protein Pept Sci. 2018; 19(6):612-622 [PubMed
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Clusterin is a multifunctional glycoprotein whose role in cells has generated a great controversy in recent years. Since its discovery, numerous studies have linked clusterin expression deregulation with various physio-pathological processes such as cancer or Alzheimer's disease. Although the results of such investigations have sometimes been contradictory, mainly due to the dichotomous role of clusterin isoforms, it has been demonstrated that this protein is involved in diverse cellular processes, including apoptosis, cell cycle regulation, DNA repair or the acquisition of cell resistance against multiple conventional therapies. These results, together with the breakthrough of gene therapies, have motivated a great effort to elucidate the importance of clusterin as a potential therapeutic target. However, the understanding of a single gene, with multiple RNA transcripts and several protein isoforms has turned out to be a complex task. In this review, we summarize the studies published to date on factors that can affect clusterin expression and evaluate if a better understanding of this complex gene/protein would be useful to develop new treatment strategies for cancer and other pathologies.
Vange P, Bruland T, Doseth B, et al.The cytoprotective protein clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and promotes gastric cancer cell survival.
PLoS One. 2017; 12(9):e0184514 [PubMed
] Free Access to Full Article Related Publications
The cytoprotective protein clusterin is often dysregulated during tumorigenesis, and in the stomach, upregulation of clusterin marks emergence of the oxyntic atrophy (loss of acid-producing parietal cells)-associated spasmolytic polypeptide-expressing metaplasia (SPEM). The hormone gastrin is important for normal function and maturation of the gastric oxyntic mucosa and hypergastrinemia might be involved in gastric carcinogenesis. Gastrin induces expression of clusterin in adenocarcinoma cells. In the present study, we examined the expression patterns and gastrin-mediated regulation of clusterin in gastric tissue from: humans; rats treated with proton pump (H+/K+-ATPase) inhibitors and/or a gastrin receptor (CCK2R) antagonist; H+/K+-ATPase β-subunit knockout (H/K-β KO) mice; and Mongolian gerbils infected with Helicobacter pylori and given a CCK2R antagonist. Biological function of secretory clusterin was studied in human gastric cancer cells. Clusterin was highly expressed in neuroendocrine cells in normal oxyntic mucosa of humans and rodents. In response to hypergastrinemia, expression of clusterin increased significantly and its localization shifted to basal groups of proliferative cells in the mucous neck cell-chief cell lineage in all animal models. That shift was partially inhibited by antagonizing the CCK2R in rats and gerbils. The oxyntic mucosa of H/K-β KO mice contained areas with clusterin-positive mucous cells resembling SPEM. In gastric adenocarcinomas, clusterin mRNA expression was higher in diffuse tumors containing signet ring cells compared with diffuse tumors without signet ring cells, and clusterin seemed to be secreted by tumor cells. In gastric cancer cell lines, gastrin increased secretion of clusterin, and both gastrin and secretory clusterin promoted survival after starvation- and chemotherapy-induced stress. Overall, our results indicate that clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and stimulates gastric cancer cell survival.
Pharmacological levels of ascorbate have long been suggested as a potential treatment of cancer. However, we observed that EC50 of ascorbate was at a similar level for cultured healthy melanocytes and melanoma cells, suggesting a limit of pharmacological ascorbate in treating cancer. Loss of 5-hydroxymethylcytosine (5 hmC) is an epigenetic hallmark of cancer and ascorbate promotes 5 hmC generation by serving as a cofactor for TET methylcytosine dioxygenases. Our previous work demonstrated that ascorbate treatment at physiological level (100 μM) increased 5 hmC content in melanoma cells toward the level of healthy melanocytes. Here we show that 100 µM of ascorbate induced apoptosis in A2058 melanoma cells. RNA-seq analysis revealed that expression of the Clusterin (CLU) gene, which is related to apoptosis, was downregulated by ascorbate. The suppression of CLU was verified at transcript level in different melanoma cell lines, and at protein level in A2058 cells. The anti-apoptotic cytoplasmic CLU was decreased, while the pro-apoptotic nuclear CLU was largely maintained, after ascorbate treatment. These changes in CLU subcellular localization were also associated with Bax and caspases activation, Bcl-xL sequestration, and cytochrome c release. Taken together, this study establishes an impending therapeutic role of physiological ascorbate to potentiate apoptosis in melanoma.
Mutlu A, Ozturk M, Akpinar G, et al.Proteomics analysis of pleomorphic adenoma of the human parotid gland.
Eur Arch Otorhinolaryngol. 2017; 274(8):3183-3195 [PubMed
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The objective of this study is to perform proteomic analysis of pleomorphic adenoma (PA) in the human parotid gland (PG) with comparison of normal PG. This is an individual prospective randomized controlled trial. This study was performed in a tertiary referral center. Tissue samples of PG and PA were taken after surgical excision of PG from 13 patients. Protein extracts were prepared and protein pools created from the soluble extracts were subjected to 2D-DIGE analysis. Proteins displaying regulation in their abundance were determined and identified using MALDIT-OF/TOF analysis. The identified proteins were subjected to STRING analysis for classification of the proteins based on their biological roles in metabolic pathways. Fifteen proteins, carbonic anhydrase 1, carbonic anhydrase 2, fibrinogen beta chain, alpha-amylase 1, heats hock protein hsp 90-alpha, clusterin, 78 kDa glucose-regulated protein, endoplasmin, alpha-amylase 2b, ATP synthase subunit alpha (mitochondrial), elongation factor 1-gamma, malate dehydrogenase, cytoplasmic, triosephosphate isomerase, receptor of activated protein c kinase 1, and aconitate hydratase, mitochondrial were down-regulated, whereas 11 proteins including ig kappa chain c region, serotransferrin, vimentin, annexin a5, glial fibrillary acidic protein, calreticulin, cartilage oligomeric matrix protein, microfibril-associated glycoprotein 4, 14-3-3 protein epsilon, fibulin-5, and f-box only protein 2 were up-regulated in PA samples in comparison to healthy parotid tissue. This study described the differences observed in protein expression patterns of the PA and normal PG. The results may provide new insights into the pathogenesis and diagnosis of PA in human PG.
LEVEL OF EVIDENCE: 1b.
Wang X, Xie J, Lu X, et al.Melittin inhibits tumor growth and decreases resistance to gemcitabine by downregulating cholesterol pathway gene CLU in pancreatic ductal adenocarcinoma.
Cancer Lett. 2017; 399:1-9 [PubMed
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Melittin is a Chinese traditional medicine for treating chronic inflammation, immunological diseases and cancers, however, the efficacy of melittin and its mechanism for treating pancreatic ductal adenocarcinoma (PDAC) are still unknown. Here we investigated the anti-cancer activity of melittin and its regulated mechanism(s) in the PDAC models. Melittin was found to suppress tumor growth by promoting cell apoptosis and cell-cycle arrest. Interestingly, the microarray analyses demonstrated that melittin significantly regulated cholesterol biosynthesis pathway during treatment. For instance, the cholesterol pathway gene clusterin (CLU) was highly downregulated by melittin which also enhanced gemcitabine sensitivity in PDAC cells by inhibiting CLU expression. In contrast, overexpression of CLU significantly diminished melittin mediated tumor suppression and gemcitabine sensitization, suggesting that CLU is the target of melittin. Furthermore, in the xenograft mouse model, the combination therapy of melittin and gemcitabine is more efficacious for inhibiting PDAC tumor growth than either single regimen. Taken together, our study has indicated that melittin is capable of suppressing tumor growth and promoting gemcitabine sensitivity in PDAC by downregulating cholesterol pathway.
Huang C, Qin Y, Liu H, et al.Downregulation of a novel long noncoding RNA TRPM2-AS promotes apoptosis in non-small cell lung cancer.
Tumour Biol. 2017; 39(2):1010428317691191 [PubMed
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Non-small cell lung cancer is one of the most common types of cancer, and the prognosis of non-small cell lung cancer is still poor. Recent evidence has proved that long noncoding RNA is involved in tumorigenesis. For non-small cell lung cancer, the expression profile of long noncoding RNA has been studied. Here, we identified a novel long noncoding RNA TRPM2-AS from published dataset and found TRPM2-AS is widely upregulated in non-small cell lung cancer tissues compared with adjacent non-tumor tissues. Higher expression level of TRPM2-AS was correlated with higher TNM stages and larger tumor size. Patients with high TRPM2-AS expression level had poor survival than those with low TRPM2-AS level. We silenced TRPM2-AS by small interfering RNA and found that cell proliferation was significantly inhibited after knockdown of TRPM2-AS. Annexin V/propidium iodide staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay confirmed that cell apoptosis increased after TRPM2-AS knockdown. Further experiments showed that silence of TRPM2-AS upregulated SHC1 and silence of SHC1 partially reversed cell apoptosis after TRPM2-AS knockdown. In summary, the novel long noncoding RNA TRPM2-AS upregulated in non-small cell lung cancer, and downregulation of TRPM2-AS promotes apoptosis in vitro.
Yoo MW, Park J, Han HS, et al.Discovery of gastric cancer specific biomarkers by the application of serum proteomics.
Proteomics. 2017; 17(6) [PubMed
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Current diagnostic markers for gastric cancer are not sufficiently specific or sensitive for use in clinical practice. The aims of this study are to compare the proteomes of serum samples from patients with gastric cancers and normal controls, and to develop useful tumor markers of gastric cancer by quantitative proteomic analysis. We identified a total of 388 proteins with a ≤1% FDR and with at least two unique peptides from the sera of each group. Among them, 215, 251, and 260 proteins were identified in serum samples of patients in an advanced cancer group, early cancer group, and normal control group, respectively. We selected differentially expressed proteins in cancer patients compared with those of normal controls via semiquantitative analyses comparing the spectral counts of identified proteins. These differentially expressed proteins were successfully verified using an MS-based quantitative assay, multiple reactions monitoring analysis. Four proteins (vitronectin, clusterin isoform 1, thrombospondin 1, and tyrosine-protein kinase SRMS) were shown to have significant changes between the cancer groups and the normal control group. These four serum proteins were able to discriminate gastric cancer patients from normal controls with sufficient specificity and selectivity.
PURPOSE: Discovery and development of a novel anticancer PEG-SMR-Clu peptide to prevent breast cancer metastasis. How breast cancer cells and primary mammary epithelial cells interact and communicate with each other to promote tumorigenesis and how to prevent tumor metastasis has long been a concern of researchers. Cancer cells secrete exosomes containing proteins and RNA. These factors can influence tumor development by directly targeting cancer cells and tumor stroma. In this study, we determined the effects of a peptide as an inhibitor of exosome secretion on breast tumors. We developed a peptide derived from the Secretion Modification Region (SMR) of HIV-1 Nef protein that was modified with PEG on the N-terminus and with a Clusterin (Clu)-binding peptide on the C-terminus. Attachment of PEG to the SMR peptide, termed PEGylation, offers improved water solubility and stability as well as reduced clearance through the kidneys, leading to a longer circulation time. The 12-mer Clu-binding peptide plays multiple roles in tumor development and metastasis. The Clu peptide can be detected by antibody in vivo, thus it has the potential to be used to monitor tumor status and treatment efficacy in animal studies and eventually in cancer patients.
RESULTS: PEG-SMRwt-Clu and PEG-SMRwt peptides inhibited the growth of both of MCF-7 (estrogen responsive, ER+) and MDA-MD-231 (estrogen non-responsive, ER-) human breast cancer cells in a dose and time-dependent manner, without inducing cytotoxic effects. The SMRwt peptide, combined with paclitaxel, induced G2/M phase cell cycle arrest on MCF-7 and MDA-MB-231 cells but did not promote apoptosis. PEG-SMRwt-Clu peptide treatment blocked exosome release from both MCF-7 and MDA-MB-231 cells. This effect was blocked by knockdown of the chaperone protein mortalin by either antibody or siRNA.
MATERIALS AND METHODS: MCF-7 and MDA-MB-231 breast tumor cells were treated with PEG-SMR-Clu peptide alone and in combination with paclitaxel and cisplatin. Cell proliferation and viabilty were determined via cell cycle analysis using Cellometer imaging cytometry, Annexin V and MTT assays. The effects of the PEG-SMR-Clu peptide on tumor exosome release were determined by testing isolated exosome fractions, for (i) expression of CD63 and Alix proteins by Western blotting, (ii) NanoSight nanoparticle tracking analysis (NTA 10) to measure exosomes size and concentration, and (iii) measurement of acetylcholinesterase (AchE) for exosome specific enzyme activity.
CONCLUSIONS: PEG-SMRwt-CLU peptides inhibited the growth of human breast cancer cells and blocked tumor exosome release in vitro. The peptide alone did not cause increased cytotoxicity or apoptosis induction, but did cause cell cycle G2/M phase arrest in both estrogen responsive and non-responsive breast cancer cells. These data suggest a potential therapeutic value of SMR to prevent breast cancer metastasis and as an adjuvant for the chemotherapeutic treatment of human breast cancer.
TRPM2, one member of the transient receptor potential (TRP) protein super-family, is a Ca
Alexiev BA, Tumer Y, Yang GYMalignant tenosynovial giant cell tumor with CDKN2A/B genomic alteration: a histological, immunohistochemical, and molecular study.
Hum Pathol. 2017; 63:144-148 [PubMed
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Diffuse-type tenosynovial giant cell tumor (D-T TSGCT) is regarded as a benign but locally aggressive neoplasm with significant recurrent potential. We report a case of malignant D-T TSGCT with pleural metastases arising in the left knee in a 57-year-old man. The tumor demonstrated atypical features, including a solid infiltrative pattern with spindling of the tumor cells, nuclear pleomorphism with prominent nucleoli, and markedly increased mitotic activity (>20 mitoses/10 high-power fields). The immunoprofile demonstrated clusterin+, D2-40+, CD68+, p63+, MDM2+, and p16+ tumor. The next-generation sequencing-based assay demonstrated loss of the CDKN2A/B gene. Pleural metastases with identical histologic and immunohistochemical features were identified 2 years later after primary tumor resection. To the best of our knowledge, this is the first reported case of D-T TSGCT with CDKN2A/B genomic alteration, MDM2 expression, and p16 loss. Clinicians and pathologists should be aware of the morphologic variability and the metastatic propensity of this entity.
Wilson MR, Zoubeidi AClusterin as a therapeutic target.
Expert Opin Ther Targets. 2017; 21(2):201-213 [PubMed
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INTRODUCTION: Clusterin (CLU) is a stress-activated, ATP-independent molecular chaperone, normally secreted from cells, that is up-regulated in Alzheimer disease and in many cancers. It plays important roles in protein homeostasis/proteostasis, inhibition of cell death pathways, and modulation of pro-survival signalling and transcriptional networks. Changes in the CLU gene locus are highly associated with Alzheimer disease, and many therapy-resistant cancers over-express CLU. The extensive post-translational processing and heterogeneous oligomerization of CLU have so far prevented any definitive structure determination. This in turn has meant that targeting CLU with small molecule inhibitors is challenging. Therefore, inhibiting CLU at the gene-expression level using siRNA or antisense is a valid approach to inhibit its function. Areas covered: This article reviews recent advances regarding the role of CLU in proteostasis, cellular trafficking, human diseases, and signalling pathways involved in oncogenesis. It addresses the rationale for CLU as a therapeutic target in cancer, and the current status of pre-clinical and clinical studies using CLU antisense inhibitor OGX011. Expert opinion: Discusses challenges facing the therapeutic targeting of CLU including rapid changes in the treatment landscape for prostate cancer with multiple new FDA approved drugs, selection of windows of intervention, and potential side effects when silencing CLU expression.
Tellez T, Garcia-Aranda M, Redondo MThe Role of Clusterin in Carcinogenesis and its Potential Utility as Therapeutic Target.
Curr Med Chem. 2016; 23(38):4297-4308 [PubMed
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Clusterin is a glycoprotein that has been implicated in many processes, including apoptosis, cell cycle regulation and DNA repair. Since clusterin expression has also been associated with tumorigenesis and the progression of various malignancies including prevalent tumors like prostate, colon, bladder and breast, this protein has been proposed as a good candidate for future treatments. There have been numerous studies conducted in cell lines and xenograft models with successful results that, in general, justify the use of clusterin as a therapeutic target. However, it is still necessary to continue with these studies in order to achieve a better understanding of the role of this protein in carcinogenesis and to determine those specific situations in which its therapeutic use may be more favorable. In this review, we will make a brief description of clusterin structure and genetics, its implication in tumorigenesis and cancer progression and its prognosis utility. Finally, we will analyze the effects of clusterin inhibition in different types of cancer.