Research IndicatorsGraph generated 17 August 2015 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 17 August, 2015 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
TICdb, Universidad de Navarra
Search the database of Translocation breakpoints In Cancer for "SFPQ"
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: SFPQ (cancer-related)
Lu B, Wang C, Zhang J, et al.Perivascular epithelioid cell tumor of gastrointestinal tract: case report and review of the literature.
Medicine (Baltimore). 2015; 94(3):e393 [PubMed
] Related Publications
Perivascular epithelioid cell tumors of gastrointestinal tract (GI PEComas) are exceedingly rare, with only a limited number of published reports worldwide. Given the scarcity of GI PEComas and their relatively short follow-up periods, our current knowledge of their biologic behavior, molecular genetic alterations, diagnostic criteria, and prognostic factors continues to be very limited.We present 2 cases of GI PEComas, one of which showed an aggressive histologic behavior that underwent multiple combined chemotherapies. We also review the available English-language medical literature on GI PEComas-not otherwise specified (PEComas-NOS) and discuss their clinicopathological and molecular genetic features.Pathologic analyses including histomorphologic, immunohistochemical, and ultrastructural studies were performed to evaluate the clinicopathological features of GI PEComas, their diagnosis, and differential diagnosis. Immunohistochemistry, semiquantitative reverse transcriptase polymerase chain reaction, and DNA sequencing assays were carried out to detect the potential molecular genetic alterations in our cases. Microscopically, the tumors showed distinctive histologic features of PEComas-NOS, including fascicular or nested architecture, epithelioid or spindled cell type, and clear to eosinophilic cytoplasm. The tumor cells were immunohistochemically positive for melanocytic markers. Molecular pathological assays confirmed a PSF-TFE3 gene fusion in one of our cases. Furthermore, in this case microphthalmia-associated transcription factor and its downstream genes were found to exhibit elevated transcript levels.Knowledge about the molecular genetic alterations in GI PEComas is still limited and warrants further study.
Fang D, Yang H, Lin J, et al.17β-estradiol regulates cell proliferation, colony formation, migration, invasion and promotes apoptosis by upregulating miR-9 and thus degrades MALAT-1 in osteosarcoma cell MG-63 in an estrogen receptor-independent manner.
Biochem Biophys Res Commun. 2015; 457(4):500-6 [PubMed
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In bone, different concentration of estrogen leads to various of physiological processes in osteoblast, such as the proliferation, migration, and apoptosis in an estrogen receptor-dependent manner. But little was known about the estrogen effects on osteosarcoma (OS). In this study, OS cell MG-63 was treated with low (1 nM) or high (100 nM) dose of 17β-Estradiol (E2) with the presence or absence of estrogen receptor α (ERα), for evaluating the E2 effects on proliferation, migration, invasion, colony formation and apoptosis. Consistent with a previous study, high dose of E2 treatment dramatically downregulated expressing level of long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT-1). The observation of upregulation of miR-9 after a high dose of E2 treatment indicated the cause of MALAT-1 reduction. Downregulation of MALAT-1 promoted the combination of SFPQ/PTBP2 complex. It was also observed that the proliferation, migration, invasion, colony formation and apoptosis of OS cells were remarkably affected by high dose of E2 treatment, but not by low dose, in an ERα independent manner. Furthermore, the abolishment of the effects on these physiological processes caused by ectopic expression of miR-9 ASOs suggested the necessity of miR-9 in MALAT-1 regulation. Here we found that the high dose of E2 treatment upregulated miR-9 thus posttranscriptionally regulated MALAT-1 RNA level in OS cells, and then the downregulation of MALAT-1 inhibited cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) processes in the E2-dose dependent and ER-independent ways.
Zhan HQ, Chen H, Wang CF, Zhu XZA case of PSF-TFE3 gene fusion in Xp11.2 renal cell carcinoma with melanotic features.
Hum Pathol. 2015; 46(3):476-81 [PubMed
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Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) with PSF-TFE3 gene fusion is a rare neoplasm. Only 22 cases of Xp11.2 RCCs with PSF-TFE3 have been reported to date. We describe an additional case of Xp11.2 RCC with PSF-TFE3 showing melanotic features. Microscopically, the histologic features mimic clear cell renal cell carcinoma. However, the dark-brown pigments were identified and could be demonstrated as melanins. Immunohistochemically, the tumor cells were widely positive for CD10, human melanoma black 45, and TFE3 but negative for cytokeratins, vimentin, Melan-A, microphthalmia-associated transcription factor, smooth muscle actin, and S-100 protein. Genetically, we demonstrated PSF-TFE3 fusion between exon 9 of PSF and exon 5 of TFE3. The patient was free of disease with 50 months of follow-up. The prognosis of this type of tumor requires more cases because of limited number of cases and follow-up period. Xp11.2 RCC with PSF-TFE3 inevitably requires differentiation from other kidney neoplasms. Immunohistochemical and molecular genetic analyses are essential for accurate diagnosis.
Ji Q, Zhang L, Liu X, et al.Long non-coding RNA MALAT1 promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2 complex.
Br J Cancer. 2014; 111(4):736-48 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) is a functional long non-coding RNA (lncRNA), which is highly expressed in several tumours, including colorectal cancer (CRC). Its biological function and mechanism in the prognosis of human CRC is still largely under investigation.
METHODS: This study aimed to investigate the new effect mechanism of MALAT1 on the proliferation and migration of CRC cells in vitro and in vivo, and detect the expression of MALAT1, SFPQ (also known as PSF (PTB-associated splicing factor)), and PTBP2 (also known as PTB (polypyrimidine-tract-binding protein)) in CRC tumour tissues, followed by correlated analysis with clinicopathological parameters.
RESULTS: We found that overexpression of MALAT1 could promote cell proliferation and migration in vitro, and promote tumour growth and metastasis in nude mice. The underlying mechanism was associated with tumour suppressor gene SFPQ and proto-oncogene PTBP2. In CRC, MALAT1 could bind to SFPQ, thus releasing PTBP2 from the SFPQ/PTBP2 complex. In turn, the increased SFPQ-detached PTBP2 promoted cell proliferation and migration. SFPQ critically mediated the regulatory effects of MALAT1. Moreover, in CRC tissues, MALAT1 and PTBP2 were overexpressed, both of which were associated closely with the invasion and metastasis of CRC. However, the SFPQ showed unchanged expression either in CRC tissues or adjacent normal tissues.
CONCLUSIONS: Our findings implied that MALAT1 might be a potential predictor for tumour metastasis and prognosis. Furthermore, the interaction between MALAT1 and SFPQ could be a novel therapeutic target for CRC.
Cho S, Moon H, Loh TJ, et al.PSF contacts exon 7 of SMN2 pre-mRNA to promote exon 7 inclusion.
Biochim Biophys Acta. 2014; 1839(6):517-25 [PubMed
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Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease and a leading cause of infant mortality. Deletions or mutations of SMN1 cause SMA, a gene that encodes a SMN protein. SMN is important for the assembly of Sm proteins onto UsnRNA to UsnRNP. SMN has also been suggested to direct axonal transport of β-actin mRNA in neurons. Humans contain a second SMN gene called SMN2 thus SMA patients produce some SMN but not with sufficient levels. The majority of SMN2 mRNA does not include exon 7. Here we show that increased expression of PSF promotes inclusion of exon 7 in the SMN2 whereas reduced expression of PSF promotes exon 7 skipping. In addition, we present evidence showing that PSF interacts with the GAAGGA enhancer in exon 7. We also demonstrate that a mutation in this enhancer abolishes the effects of PSF on exon 7 splicing. Furthermore we show that the RNA target sequences of PSF and tra2β in exon 7 are partially overlapped. These results lead us to conclude that PSF interacts with an enhancer in exon 7 to promote exon 7 splicing of SMN2 pre-mRNA.
TFE3 translocation renal cell carcinoma (tRCC) is defined by chromosomal translocations involving the TFE3 transcription factor at chromosome Xp11.2. Genetically proven TFE3 tRCCs have a broad histologic spectrum with overlapping features to other renal tumor subtypes. In this study, we aimed for characterizing RCC with TFE3 protein expression. Using next-generation whole transcriptome sequencing (RNA-Seq) as a discovery tool, we analyzed fusion transcripts, gene expression profile, and somatic mutations in frozen tissue of one TFE3 tRCC. By applying a computational analysis developed to call chimeric RNA molecules from paired-end RNA-Seq data, we confirmed the known TFE3 translocation. Its fusion partner SFPQ has already been described as fusion partner in tRCCs. In addition, an RNA read-through chimera between TMED6 and COG8 as well as MET and KDR (VEGFR2) point mutations were identified. An EGFR mutation, but no chromosomal rearrangements, was identified in a control group of five clear cell RCCs (ccRCCs). The TFE3 tRCC could be clearly distinguished from the ccRCCs by RNA-Seq gene expression measurements using a previously reported tRCC gene signature. In validation experiments using reverse transcription-PCR, TMED6-COG8 chimera expression was significantly higher in nine TFE3 translocated and six TFE3-expressing/non-translocated RCCs than in 24 ccRCCs (P < .001) and 22 papillary RCCs (P < .05-.07). Immunohistochemical analysis of selected genes from the tRCC gene signature showed significantly higher eukaryotic translation elongation factor 1 alpha 2 (EEF1A2) and Contactin 3 (CNTN3) expression in 16 TFE3 translocated and six TFE3-expressing/non-translocated RCCs than in over 200 ccRCCs (P < .0001, both).
Our previous study demonstrated that PTB-associated splicing factor (PSF) is an important regulator of cell death and plays critical roles in the survival and growth of colon cancer cells. However, the molecular mechanism that activates these downstream signaling events remains unknown. To address this issue, we investigated the effects of PSF knockdown in two different colon cancer cell lines, DLD-1 and HT-29. We found that knockdown of PSF markedly decreased the autophagic molecule LC3B in DLD-1 cells but not in HT-29 cells. Furthermore, DLD-1 cells were more susceptible to PSF knockdown-induced cell growth inhibition and apoptosis than HT-29 cells. This susceptibility is probably a result of LC3B inhibition, given the known relationship between autophagy and apoptosis. C3B is associated with a number of physiological processes, including cell growth and apoptotic cell death. Our results suggest that autophagy is inhibited by PSF knockdown and that apoptosis and cell growth inhibition may act together to mediate the PSF-LC3B signaling pathway. Furthermore, we found that the peroxisome proliferator-activated receptor gamma (PPARγ)-PSF complex induced LC3B downregulation in DLD-1 cells. The results of this study identify a new physiological role for the PSF-LC3B axis as a potential endogenous modulator of colon cancer treatment.
AIM: Early diagnosis of prostate cancer (PCa), which is a clinically heterogeneous-multifocal disease, is essential to improve the prognosis of patients. However, published PCa diagnostic markers share little overlap and are poorly validated using independent data. Therefore, we here developed an integrative proteomics and interaction network-based classifier by combining the differential protein expression with topological features of human protein interaction networks to enhance the ability of PCa diagnosis.
METHODS AND RESULTS: By two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with MS using PCa and adjacent benign tissues of prostate, a total of 60 proteins with the differential expression in PCa tissues were identified as the candidate markers. Then, their networks were analyzed by GeneGO Meta-Core software and three hub proteins (PTEN, SFPQ and HDAC1) were chosen. After that, a PCa diagnostic classifier was constructed by support vector machine (SVM) modeling based on the microarray gene expression data of the genes which encode the hub proteins mentioned above. Validations of diagnostic performance showed that this classifier had high predictive accuracy (85.96∼90.18%) and area under ROC curve (approximating 1.0). Furthermore, the clinical significance of PTEN, SFPQ and HDAC1 proteins in PCa was validated by both ELISA and immunohistochemistry analyses. More interestingly, PTEN protein was identified as an independent prognostic marker for biochemical recurrence-free survival in PCa patients according to the multivariate analysis by Cox Regression.
CONCLUSIONS: Our data indicated that the integrative proteomics and interaction network-based classifier which combines the differential protein expression and topological features of human protein interaction network may be a powerful tool for the diagnosis of PCa. We also identified PTEN protein as a novel prognostic marker for biochemical recurrence-free survival in PCa patients.
High-throughput techniques have identified numerous antisense (AS) transcripts and long non-coding RNAs (ncRNAs). However, their significance in cancer biology remains largely unknown. Here, we report an androgen-responsive long ncRNA, CTBP1-AS, located in the AS region of C-terminal binding protein 1 (CTBP1), which is a corepressor for androgen receptor. CTBP1-AS is predominantly localized in the nucleus and its expression is generally upregulated in prostate cancer. CTBP1-AS promotes both hormone-dependent and castration-resistant tumour growth. Mechanistically, CTBP1-AS directly represses CTBP1 expression by recruiting the RNA-binding transcriptional repressor PSF together with histone deacetylases. CTBP1-AS also exhibits global androgen-dependent functions by inhibiting tumour-suppressor genes via the PSF-dependent mechanism thus promoting cell cycle progression. Our findings provide new insights into the functions of ncRNAs that directly contribute to prostate cancer progression.
Zhong M, Weisman P, Zhu B, et al.Xp11.2 translocation renal cell carcinoma with PSF-TFE3 rearrangement.
Diagn Mol Pathol. 2013; 22(2):107-11 [PubMed
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Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) is a subtype of RCC characterized by translocations involving a breakpoint at the TFE3 gene (Xp11.2). Moderate to strong nuclear TFE3 immunoreactivity has been recognized as a specific diagnostic marker for this type of tumor. However, exclusive cytoplasmic localization of a TFE3 fusion protein was reported in UOK 145 cells, a cell line derived from an Xp11.2 RCC harboring the PSF-TFE3 translocation. If reproducible using immunohistochemistry (IHC), this finding would have important implications for pathologists in the diagnosis of Xp11.2 RCC, calling into question the specificity of nuclear immunoreactivity for TFE3 in these tumors. The purpose of this study was to determine whether the above-noted cytoplasmic localization of the TFE3 fusion protein could be reproduced using IHC. UOK 145 cells and fresh frozen tissue from 2 clinical cases of Xp11.2 RCC found to harbor the PSF-TFE3 gene rearrangement (by cytogenetic testing) were collected. All samples were subjected to histopathologic evaluation by board-certified pathologists, TFE3 IHC, reverse transcription polymerase chain reaction, and Sanger sequencing analysis. A strong nuclear TFE3 immunoreactivity was demonstrated in all samples including the UOK 145 cell line. No cytoplasmic immunoreactivity was seen. Reverse transcription polymerase chain reaction and Sanger sequencing confirmed the previously reported PSF-TFE3 gene fusion between exon 9 of PSF and exon 6 of TFE3 in the UOK 145 cell line and in one of 2 clinical cases of Xp11.2 RCC. A novel PSF-TFE3 gene fusion between exon 9 of PSF and exon 5 of TFE3 was detected in the second clinical case of Xp11.2 RCC.
Wu CF, Tan GH, Ma CC, Li LThe non-coding RNA llme23 drives the malignant property of human melanoma cells.
J Genet Genomics. 2013; 40(4):179-88 [PubMed
] Related Publications
Several lines of evidence support the notion that increased RNA-binding ability of polypyrimidine tract-binding (PTB) protein-associated splicing factor (PSF) and aberrant expression of long non-coding RNAs (lncRNAs) are associated with mouse and human tumors. To identify the PSF-binding lncRNA involved in human oncogenesis, we screened a nuclear RNA repertoire of human melanoma cell line, YUSAC, through RNA-SELEX affinity chromatography. A previously unreported lncRNA, termed as Llme23, was found to bind immobilized PSF resin. The specific binding of Llme23 to both recombinant and native PSF protein was confirmed in vitro and in vivo. The expression of PSF-binding Llme23 is exclusively detected in human melanoma lines. Knocking down Llme23 remarkably suppressed the malignant property of YUSAC cells, accompanied by the repressed expression of proto-oncogene Rab23. These results may indicate that Llme23 can function as an oncogenic RNA and directly associate the PSF-binding lncRNA with human melanoma.
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that plays an essential role in cell proliferation, apoptosis, and inflammation. It is over-expressed in many types of cancer, including colon, stomach, breast, and lung cancer, suggesting that regulation of PPARγ might affect cancer pathogenesis. Here, using a proteomic approach, we identify PTB-associated splicing factor (PSF) as a novel PPARγ-interacting protein and demonstrate that PSF is involved in several important regulatory steps of colon cancer cell proliferation. To investigate the relationship between PSF and PPARγ in colon cancer, we evaluated the effects of PSF expression in DLD-1 and HT-29 colon cancer cell lines, which express low and high levels of PPARγ, respectively PSF affected the ability of PPARγ to bind, and expression of PSF siRNA significantly suppressed the proliferation of colon cancer cells. Furthermore, PSF knockdown induced apoptosis via activation of caspase-3. Interestingly, DLD-1 cells were more susceptible to PSF knockdown-induced cell death than HT-29 cells. Our data suggest that PSF is an important regulator of cell death that plays critical roles in the survival and growth of colon cancer cells. The PSF-PPARγ axis may play a role in the control of colorectal carcinogenesis. Taken together, this study is the first to describe the effects of PSF on cell proliferation, tumor growth, and cell signaling associated with PPARγ.
Kobos R, Nagai M, Tsuda M, et al.Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein.
J Pathol. 2013; 229(5):743-54 [PubMed
] Free Access to Full Article Related Publications
Oncogenic rearrangements of the TFE3 transcription factor gene are found in two distinct human cancers. These include ASPSCR1-TFE3 in all cases of alveolar soft part sarcoma (ASPS) and ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3 and others in a subset of paediatric and adult RCCs. Here we examined the functional properties of the ASPSCR1-TFE3 fusion oncoprotein, defined its target promoters on a genome-wide basis and performed a high-throughput RNA interference screen to identify which of its transcriptional targets contribute to cancer cell proliferation. We first confirmed that ASPSCR1-TFE3 has a predominantly nuclear localization and functions as a stronger transactivator than native TFE3. Genome-wide location analysis performed on the FU-UR-1 cell line, which expresses endogenous ASPSCR1-TFE3, identified 2193 genes bound by ASPSCR1-TFE3. Integration of these data with expression profiles of ASPS tumour samples and inducible cell lines expressing ASPSCR1-TFE3 defined a subset of 332 genes as putative up-regulated direct targets of ASPSCR1-TFE3, including MET (a previously known target gene) and 64 genes as down-regulated targets of ASPSCR1-TFE3. As validation of this approach to identify genuine ASPSCR1-TFE3 target genes, two up-regulated genes bound by ASPSCR1-TFE3, CYP17A1 and UPP1, were shown by multiple lines of evidence to be direct, endogenous targets of transactivation by ASPSCR1-TFE3. As the results indicated that ASPSCR1-TFE3 functions predominantly as a strong transcriptional activator, we hypothesized that a subset of its up-regulated direct targets mediate its oncogenic properties. We therefore chose 130 of these up-regulated direct target genes to study in high-throughput RNAi screens, using FU-UR-1 cells. In addition to MET, we provide evidence that 11 other ASPSCR1-TFE3 target genes contribute to the growth of ASPSCR1-TFE3-positive cells. Our data suggest new therapeutic possibilities for cancers driven by TFE3 fusions. More generally, this work establishes a combined integrated genomics/functional genomics strategy to dissect the biology of oncogenic, chimeric transcription factors.
Ohe C, Kuroda N, Hes O, et al.A renal epithelioid angiomyolipoma/perivascular epithelioid cell tumor with TFE3 gene break visualized by FISH.
Med Mol Morphol. 2012; 45(4):234-7 [PubMed
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We present a case of renal epithelioid angiomyolipoma (eAML)/perivascular epithelioid cell tumor (PEComa) with a TFE3 gene break visible by fluorescence in situ hybridization (FISH). Histologically, the tumor was composed of mainly epithelioid cells forming solid arrangements with small foci of spindle cells. In a small portion of the tumor, neoplastic cells displayed nuclear pleomorphism, such as polygonal and enlarged vesicular nuclei with prominent nucleoli. Marked vascularity was noticeable in the background, and perivascular hyaline sclerosis was also seen. Immunohistochemically, neoplastic cells were diffusely positive for α-smooth muscle actin and melanosome in the cytoplasm. Nuclei of many neoplastic cells were positive for TFE3. FISH analysis of the TFE3 gene break using the Poseidon TFE3 (Xp11) Break probe revealed positive results. Reverse transcriptase-polymerase chain reactions (RT-PCR) for ASPL/TFE3, PRCC/TFE3, CLTC/TFE3, PSF/TFE3, and NonO/TFE3 gene fusions all revealed negative results. This is the first reported case of renal eAML/PEComa with a TFE3 gene break, and it has unique histological findings as compared to previously reported TFE3 gene fusion-positive PEComas. Pathologists should recognize that PEComa with TFE3 gene fusion can arise even in the kidney.
Dolnik A, Engelmann JC, Scharfenberger-Schmeer M, et al.Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing.
Blood. 2012; 120(18):e83-92 [PubMed
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Acute myeloid leukemia (AML) is characterized by molecular heterogeneity. As commonly altered genomic regions point to candidate genes involved in leukemogenesis, we used microarray-based comparative genomic hybridization and single nucleotide polymorphism profiling data of 391 AML cases to further narrow down genomic regions of interest. Targeted resequencing of 1000 genes located in the critical regions was performed in a representative cohort of 50 AML samples comprising all major cytogenetic subgroups. We identified 120 missense/nonsense mutations as well as 60 insertions/deletions affecting 73 different genes (∼ 3.6 tumor-specific aberrations/AML). While most of the newly identified alterations were nonrecurrent, we observed an enrichment of mutations affecting genes involved in epigenetic regulation including known candidates like TET2, TET1, DNMT3A, and DNMT1, as well as mutations in the histone methyltransferases NSD1, EZH2, and MLL3. Furthermore, we found mutations in the splicing factor SFPQ and in the nonclassic regulators of mRNA processing CTCF and RAD21. These splicing-related mutations affected 10% of AML patients in a mutually exclusive manner. In conclusion, we could identify a large number of alterations in genes involved in aberrant splicing and epigenetic regulation in genomic regions commonly altered in AML, highlighting their important role in the molecular pathogenesis of AML.
Romano A, Calabria LF, Tavanti F, et al.Apparent diffusion coefficient obtained by magnetic resonance imaging as a prognostic marker in glioblastomas: correlation with MGMT promoter methylation status.
Eur Radiol. 2013; 23(2):513-20 [PubMed
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OBJECTIVE: To evaluate whether apparent diffusion coefficient (ADC) values can predict the status of MGMT of glioblastoma multiforme (GBM) and correlate with overall survival (OS) and progression-free survival (PFS).
METHODS: This retrospective study included 47 patients with pathologically proven glioblastoma. All of them underwent MR DWI study before surgery (mean time 1 week) and the status of methylguanine-DNA-methyltransferase (MGMT) promoter methylation was searched for. Minimum apparent diffusion coefficient (ADC) values were evaluated. OS and PSF parameters were calculated, and Student's t-test, Kaplan-Meier curves, linear and Cox regression were performed.
RESULTS: Twenty-five patients showed positive methylation of the MGMT promoter. Patients showing MGMT promoter methylation had higher minimum ADC values, and they survived longer than those without MGMT promoter methylation. The median ADCmin value of 0.80 represents the cutoff value able to distinguish between methylated and un-methylated patients. Patients showing minimum ADC values higher than 0.80 survived longer than patients with minimum ADC values lower than 0.80. A linear correlation between minimum ADC values vs. the OS and PFS was observed.
CONCLUSIONS: Minimum ADC values in glioblastoma multiforme could be used as a preoperative parameter to estimate the status of MGMT promoter methylation and the survival of patients.
BACKGROUND: Tri- and tetra-nucleotide repeats in mammalian genomes can induce formation of alternative non-B DNA structures such as triplexes and guanine (G)-quadruplexes. These structures can induce mutagenesis, chromosomal translocations and genomic instability. We wanted to determine if proteins that bind triplex DNA structures are quantitatively or qualitatively different between colorectal tumor and adjacent normal tissue and if this binding activity correlates with patient clinical characteristics.
METHODS: Extracts from 63 human colorectal tumor and adjacent normal tissues were examined by gel shifts (EMSA) for triplex DNA-binding proteins, which were correlated with clinicopathological tumor characteristics using the Mann-Whitney U, Spearman's rho, Kaplan-Meier and Mantel-Cox log-rank tests. Biotinylated triplex DNA and streptavidin agarose affinity binding were used to purify triplex-binding proteins in RKO cells. Western blotting and reverse-phase protein array were used to measure protein expression in tissue extracts.
RESULTS: Increased triplex DNA-binding activity in tumor extracts correlated significantly with lymphatic disease, metastasis, and reduced overall survival. We identified three multifunctional splicing factors with biotinylated triplex DNA affinity: U2AF65 in cytoplasmic extracts, and PSF and p54nrb in nuclear extracts. Super-shift EMSA with anti-U2AF65 antibodies produced a shifted band of the major EMSA H3 complex, identifying U2AF65 as the protein present in the major EMSA band. U2AF65 expression correlated significantly with EMSA H3 values in all extracts and was higher in extracts from Stage III/IV vs. Stage I/II colon tumors (p=0.024). EMSA H3 values and U2AF65 expression also correlated significantly with GSK3 beta, beta-catenin, and NF- B p65 expression, whereas p54nrb and PSF expression correlated with c-Myc, cyclin D1, and CDK4. EMSA values and expression of all three splicing factors correlated with ErbB1, mTOR, PTEN, and Stat5. Western blots confirmed that full-length and truncated beta-catenin expression correlated with U2AF65 expression in tumor extracts.
CONCLUSIONS: Increased triplex DNA-binding activity in vitro correlates with lymph node disease, metastasis, and reduced overall survival in colorectal cancer, and increased U2AF65 expression is associated with total and truncated beta-catenin expression in high-stage colorectal tumors.
Kurokawa K, Tanahashi T, Iima T, et al.Role of miR-19b and its target mRNAs in 5-fluorouracil resistance in colon cancer cells.
J Gastroenterol. 2012; 47(8):883-95 [PubMed
] Related Publications
BACKGROUND: Drug resistance in colorectal cancers is assumed to be mediated by changes in the expression of microRNAs, but the specific identities and roles of microRNAs are largely unclear. We examined the effect of 5-fluorouracil (5-FU) resistance on microRNA expression.
METHODS: Two types of 5-FU-resistant colon cancer cells were derived from the DLD-1 and KM12C cell lines. The expressions of microRNAs were profiled with a microarray containing 723 microRNAs and validated by quantitative real-time polymerase chain reaction (qRT-PCR). To survey the downstream mediators of microRNA, we used a microRNA:mRNA immunoprecipitation (RIP)-Chip and pathway analysis tool to identify potential direct targets of microRNA.
RESULTS: In response to 5-FU, miR-19b and miR-21 were over-expressed in 5-FU-resistant cells. Of note, miR-19b was up-regulated 3.47-fold in the DLD-1 resistant cells, which exhibited no alteration in cell cycle profiles despite exposure to 5-FU. After transfection of miR-19b, specific mRNAs were recruited to microRNA:mRNA complexes isolated with Ago2 antibody and subjected to whole-genome transcriptional analysis. In this analysis, 66 target mRNAs were enriched by at least 5.0-fold in the microRNA:mRNA complexes from DLD-1 resistant cells. Ingenuity pathway analysis of mRNA targets significantly (P < 0.05) indicated the category "Cell Cycle" as a probable area of the molecular and cellular function related with 5-FU resistance. Among candidate mRNA targets, SFPQ and MYBL2 have been linked to cell cycle functions.
CONCLUSIONS: We revealed up-regulation of miR-19b in response to 5-FU and potential targets of miR-19b mediating the cell cycle under treatment with 5-FU. Our study provides an important insight into the mechanism of 5-FU resistance in colorectal cancers.
Kuroda N, Mikami S, Pan CC, et al.Review of renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions with focus on pathobiological aspect.
Histol Histopathol. 2012; 27(2):133-40 [PubMed
] Related Publications
The concept of Xp11.2 renal cell carcinoma (RCC) was recently established as a tumor affecting 15% of RCC patients <45 years. Many patients present with advanced stage with frequent lymph node metastases. Histologically, Xp11.2 RCC is characterized by mixed papillary nested/alveolar growth pattern and tumor cells with clear and/or eosinophilic, voluminous cytoplasm. Neoplastic cells show intense nuclear immunoreactivity to TFE3, while focal immunostaining for melanocytic markers, including melanosome-associated antigen or Melan A in some cases, are also noted. Alpha smooth muscle actin and TFEB are consistently negative. Ultrastructurally, the ASPL-TFE3 RCC variant contains rhomboid crystals in the cytoplasm, similar to that observed in alveolar soft part sarcoma. The fusion of the TFE3 gene with several different genes, including ASPL(17q25), PRCC(1q21), PSF(1q34), NonO (Xq12) and CLTC (17q23) have been identified to date. The behavior of Xp11.2 RCC in children and young adults is considered as indolent even when diagnosed at advanced stage, including lymph node metastasis. However, Xp11.2 RCC in older patients behaves in a more aggressive fashion. Therapy includes nephrectomy with extended lymphadenectomy. There may be a role for new protease inhibitors in advanced inoperable disease. Further research is required to correlate clinical behavior with the expanding genetic spectrum of this tumor, and to establish standard therapy protocols for primary and metastatic lesions.
BACKGROUND: The dynamic regulation of cell-cell adhesions is crucial for developmental processes, including tissue formation, differentiation and motility. Adherens junctions are important components of the junctional complex between cells and are necessary for maintaining cell homeostasis and normal tissue architecture. E-cadherin is the prototype and best-characterized protein member of adherens junctions in mammalian epithelial cells. Regarded as a tumour suppressor, E-cadherin loss is associated with poor prognosis in carcinoma. The E3 ubiquitin-ligase Hakai was the first reported posttranslational regulator of the E-cadherin complex. Hakai specifically targetted E-cadherin for internalization and degradation and thereby lowered epithelial cell-cell contact. Hakai was also implicated in controlling proliferation, and promoted cancer-related gene expression by increasing the binding of RNA-binding protein PSF to RNAs encoding oncogenic proteins. We sought to investigate the possible implication of Hakai in cell-substratum adhesions and invasion in epithelial cells.
METHODS: Parental MDCK cells and MDCK cells stably overexpressing Hakai were used to analyse cell-substratum adhesion and invasion capabilities. Western blot and immunofluoresecence analyses were performed to assess the roles of Paxillin, FAK and Vinculin in cell-substratum adhesion. The role of the proteasome in controlling cell-substratum adhesion was studied using two proteasome inhibitors, lactacystin and MG132. To study the molecular mechanisms controlling Paxillin expression, MDCK cells expressing E-cadherin shRNA in a tetracycline-inducible manner was employed.
RESULTS: Here, we present evidence that implicate Hakai in reducing cell-substratum adhesion and increasing epithelial cell invasion, two hallmark features of cancer progression and metastasis. Paxillin, an important protein component of the cell-matrix adhesion, was completely absent from focal adhesions and focal contacts in Hakai-overexpressing MDCK cells. The expression of Paxillin was found to be regulated by a proteasome-independent mechanism, possibly due to the decreased abundance of E-cadherin.
CONCLUSIONS: Taken together, these results suggest that Hakai may be involved in two hallmark aspects of tumour progression, the lowering cell-substratum adhesion and the enhancement of cell invasion.
Cristobo I, Larriba MJ, de los Ríos V, et al.Proteomic analysis of 1α,25-dihydroxyvitamin D3 action on human colon cancer cells reveals a link to splicing regulation.
J Proteomics. 2011; 75(2):384-97 [PubMed
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1α,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and other vitamin D compounds are promising molecules in the prevention and therapy of colon cancer and other neoplasias. To study the mechanism of action of 1,25(OH)(2)D(3) in colon cancer cells, we carried out a comparative proteomic analysis of the nuclear fractions of SW480-ADH cells treated with 1,25(OH)(2)D(3) or vehicle during 8 or 48h. 2D-DIGE analysis combined with MALDI-TOF-TOF mass spectrometry interrogation led to the identification of 59 differentially expressed unique proteins. Most identified proteins were nuclear, but several cytoskeleton-associated proteins were also detected. A good concordance between changes in expression at protein and RNA levels was observed for the validated proteins. A large group of identified proteins, such as SFPQ, SMARCE, KHSRP, TARDBP and PARP1, were involved in RNA processing or modification and have been ascribed to the spliceosome compartment of human cells. In addition, a smaller group of proteins (ERM (Ezrin, Radixin, Moesin) family, VCL, CORO1C, ACTB) were cytoskeleton-associated and played a role in cell adhesion and morphology. These results confirm the induction of epithelial phenotype by 1,25(OH)(2)D(3) and suggest a role for vitamin D compounds in the regulation of the spliceosome and thus, in alternative splicing and possibly microRNA synthesis in colon cancer cells.
Brassesco MS, Valera ET, Bonilha TA, et al.Secondary PSF/TFE3-associated renal cell carcinoma in a child treated for genitourinary rhabdomyosarcoma.
Cancer Genet. 2011; 204(2):108-10 [PubMed
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Xp11.2 translocation-associated renal cell carcinoma (RCC) is a rare tumor that accounts for at least one-third of childhood RCC. Different reports have emphasized that previous radio/chemotherapy might be involved in its pathogenesis. We describe a child who developed a t(X;1)(p11.2;p34) associated RCC after previous treatment for genitourinary rhabdomyosarcoma in infancy. The presence of the PSF-TFE3 fusion has only been described in a very limited number of cases. Our report expands the spectrum of tumors in which RCC can arise in the pediatric age group after chemotherapy.
De Braekeleer E, Douet-Guilbert N, Rowe D, et al.ABL1 fusion genes in hematological malignancies: a review.
Eur J Haematol. 2011; 86(5):361-71 [PubMed
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Chromosomal rearrangements involving the ABL1 gene, leading to a BCR-ABL1 fusion gene, have been mainly associated with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia (ALL). At present, six other genes have been shown to fuse to ABL1. The kinase domain of ABL1 is retained in all chimeric proteins that are also composed of the N-terminal part of the partner protein that often includes a coiled-coil or a helix-loop-helix domain. These latter domains allow oligomerization of the protein that is required for tyrosine kinase activation, cytoskeletal localization, and neoplastic transformation. Fusion genes that have a break in intron 1 or 2 (BCR-ABL1, ETV6-ABL1, ZMIZ1-ABL1, EML1-ABL1, and NUP214-ABL1) have transforming activity, although NUP214-ABL1 requires amplification to be efficient. The NUP214-ABL1 gene is the second most prevalent fusion gene involving ABL1 in malignant hemopathies, with a frequency of 5% in T-cell ALL. Both fusion genes (SFPQ-ABL1 and RCSD1-ABL1) characterized by a break in intron 4 of ABL1 are associated with B-cell ALL, as the chimeric proteins lacked the SH2 domain of ABL1. Screening for ABL1 chimeric genes could be performed in patients with ALL, more particularly in those with T-cell ALL because ABL1 modulates T-cell development and plays a role in cytoskeletal remodeling processes in T cells.
Kuroda N, Kawada C, Tamura K, et al.Re-evaluation of histological type by immunohistochemical and genetic study of transcription factors (TFE3 and TFEB) of VHL gene mutation-negative clear cell renal cell carcinoma and other special types of renal tumor.
Med Mol Morphol. 2011; 44(1):46-51 [PubMed
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Translocation-type renal carcinoma has been recently discovered, and it is possible that this tumor may have been previously diagnosed as other types of renal tumor. We have subjected 41 renal tumors, including VHL gene mutation-negative clear cell renal cell carcinoma (RCC), papillary RCC, and chromophobe RCC, to immunohistochemistry of transcription factor E3 (TFE3) and TFEB. All tumors were histologically evaluated by additional immunohistochemical study. As a result, 5 tumors showed a positive reaction for TFE3 with a range from 1+ to 2+ in intensity. No tumors were positive for TFEB. In 5 tumors immunohistochemically positive for TFE3, chimeric transcripts including ASPL-TFE3, PRCC-TFE3, CLTCTFE3, PSF-TFE3, or Nono-TFE3 were not detected. The diagnosis of 6 tumors was changed by reevaluation through retrospective histological and immunohistochemical study. In 4 of 6 tumors, the diagnosis of clear cell RCC was changed to chromophobe RCC. In 1 tumor, oncocytoma was detectable, and RCC with rhabdoid features and sarcomatoid changes was detected in 1 tumor. Finally, the cutoff value of TFE3 immunohistochemistry should be more than 2+ with a wide range. The translocation-type renal carcinoma seems to be quite rare.
Argani P, Aulmann S, Illei PB, et al.A distinctive subset of PEComas harbors TFE3 gene fusions.
Am J Surg Pathol. 2010; 34(10):1395-406 [PubMed
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Perivascular epithelioid cell neoplasms (PEComas) include the common renal angiomyolipoma, pulmonary clear cell sugar tumor, lymphangioleiomyomatosis, and less common neoplasms of soft tissue, gynecologic, and gastrointestinal tracts. Recently, aberrant immunoreactivity for TFE3 protein (a sensitive and specific marker of neoplasms harboring TFE3 gene fusions) has been reported in as many as 100% of PEComas; however, TFE3 gene status in these neoplasms has not been systematically investigated. We used a fluorescence in situ hybridization (FISH) break-apart assay to evaluate for evidence of TFE3 gene fusions in archival material from 29 PEComas. These cases included 2 earlier published TFE3 immunoreactive nonrenal PEComas, 14 additional nonrenal PEComas, and 13 renal angiomyolipomas with predominantly spindle or epithelioid morphology. Four nonrenal PEComas (mean patient age 24 y) showed TFE3 gene rearrangements by FISH, and all 4 of these showed strong positive (3+) TFE3 immunoreactivity using the original validated overnight incubation protocol. Two of these cases had adequate mRNA for RT-PCR analysis, but neither harbored the PSF-TFE3 gene fusion reported earlier in 1 PEComa. In addition, a lung metastasis of a uterine PEComa showed TFE3 gene amplification, an earlier unreported phenomenon. None of the other 24 PEComas (mean patient age 54 y) showed TFE3 gene alterations, though 4 exhibited moderate positive (2+) TFE3 immunoreactivity. In contrast, using an automated stainer, 2 of these 4 cases exhibited strong (3+) TFE3 immunoreactivity. All PEComas with TFE3 genetic alterations immunolabeled strongly for Cathepsin K, similar to other PEComas. In conclusion, a subset of lesions currently classified as PEComas harbors TFE3 gene fusions. Although numbers are small, distinctive features of these cases include a tendency to young age, the absence of association with tuberous sclerosis, predominant alveolar architecture and epithelioid cytology, minimal immunoreactivity for muscle markers, and strong (3+) TFE3 immunoreactivity. Despite significant morphologic and immunohistochemical overlap with other PEComas, PEComas harboring TFE3 gene fusions may represent a distinctive entity.
BACKGROUND: The transcription factor Snail1 induces epithelial-to-mesenchymal transition (EMT), a process responsible for the acquisition of invasiveness during tumorigenesis. Several transcriptomic studies have reported Snail1-regulated genes in different cell types, many of them involved in cell adhesion. However, only a few studies have used proteomics as a tool for the characterization of proteins mediating EMT.
METHODOLOGY/PRINCIPAL FINDINGS: We identified by proteomic analysis using 2D-DIGE electrophoresis combined with MALDI-TOF-TOF and ESI-linear ion trap mass spectrometry a number of proteins with variable functions whose expression is modulated by Snail1 in SW480-ADH human colon cancer cells. Validation was performed by Western blot and immunofluorescence analyses. Snail1 repressed several members of the 14-3-3 family of phosphoserine/phosphothreonine binding proteins and also the expression of the Proliferation-associated protein 2G4 (PA2G4) that was mainly localized at the nuclear Cajal bodies. In contrast, the expression of two proteins involved in RNA processing, the Cleavage and polyadenylation specificity factor subunit 6 (CPSF6) and the Splicing factor proline/glutamine-rich (SFPQ), was higher in Snail1-expressing cells than in controls. The regulation of 14-3-3epsilon, 14-3-3tau, 14-3-3zeta and PA2G4 by Snail1 was reproduced in HT29 colon cancer cells. In addition, we found an inverse correlation between 14-3-3sigma and Snail1 expression in human colorectal tumors.
CONCLUSIONS/SIGNIFICANCE: We have identified a set of novel Snail1 target proteins in colon cancer that expand the cellular processes affected by Snail1 and thus its relevance for cell function and phenotype.
Hakai, an E3 ubiquitin ligase for the E-cadherin complex, plays a crucial role in lowering cell-cell contacts in epithelial cells, a hallmark feature of tumor progression. Recently, Hakai was also found to interact with PSF (PTB-associated splicing factor). While PSF can function as a DNA-binding protein with a tumor suppressive function, its association with Hakai promotes PSF's RNA-binding ability and post-transcriptional influence on target mRNAs. Hakai overexpression enhanced the binding of PSF to mRNAs encoding cancer-related proteins, while knockdown of Hakai reduced the RNA-binding ability of PSF. Furthermore, the knockdown of PSF suppressed Hakai-induced cell proliferation. Thus, Hakai can affect the oncogenic phenotype both by altering E-cadherin-based intercellular adhesions and by increasing PSF's ability to bind RNAs that promote cancer-related gene expression.
Chang IW, Huang HY, Sung MTMelanotic Xp11 translocation renal cancer: a case with PSF-TFE3 gene fusion and up-regulation of melanogenetic transcripts.
Am J Surg Pathol. 2009; 33(12):1894-901 [PubMed
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Melanotic Xp11 translocation renal cancer is a recently recognized aggressive epithelioid neoplasm with features overlapping between PEComa, carcinoma, and melanoma. We describe morphologic and immunohistochemical characteristics of a melanotic Xp11 translocation renal cancer occurring in an 18-year-old girl and perform molecular genetic studies to analyze its genetic alterations and related melanogenetic activities. The tumor was composed of solid nests of epithelioid cells bearing abundant clear to finely granular eosinophilic cytoplasm and separated by delicate vascular septa. Finely granular and nonrefractile brown melanin pigments, highlighted by Fontana-Masson stain, were scattered through the tumor. By immunohistochemistry, the tumor was diffusely and strongly labeled by TFE3 and focally stained by HMB45 in a patchy pattern. In contrast, all other applied immunomarkers, including cytokeratins, epithelial membrane antigen, vimentin, CD10, S-100, smooth muscle actin, desmin, c-kit, CD68, and microphthalmia-associated transcription factor, were nonreactive to the tumor. Reverse transcription-polymerase chain reaction and validating sequencing demonstrated PSF-TFE3 gene fusion, a novel exon composition juxtaposing PSF exon 9 to TFE3 exon 5. Up-regulations of melanogenesis-associated regulators, including microphthalmia-associated transcription factor, tyrosinase (TYR), and tyrosinase-related protein 1 (TYRP1), were identified in the tumor by semiquantitative reverse transcription-polymerase chain reaction. The morphologic and immunohistochemical discrepancies between this intriguing melanotic tumor and other documented renal cell carcinomas bearing identical PSF-TFE3 gene fusion may suggest melanotic Xp11 translocation renal cancer is a distinct entity among the MiT/TFE family neoplasms.
Wang G, Cui Y, Zhang G, et al.Regulation of proto-oncogene transcription, cell proliferation, and tumorigenesis in mice by PSF protein and a VL30 noncoding RNA.
Proc Natl Acad Sci U S A. 2009; 106(39):16794-8 [PubMed
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We describe the role of PSF protein and VL30-1 RNA, a mouse retroelement noncoding RNA, in the reversible regulation of proto-oncogene transcription, cell proliferation, and tumorigenesis in mice. The experiments involved increasing expression of PSF or VL30-1 RNA in NIH/3T3 fibroblast cells and B16F10 melanoma cells by transfecting the respective coding genes under control of a strong promoter or decreasing expression by transfecting a shRNA construct that causes degradation of PSF mRNA or VL30-1 RNA. The results are as follows: (i) PSF binds to the proto-oncogene Rab23, repressing transcription, and VL30-1 RNA binds and releases PSF from Rab23, activating transcription; (ii) increasing expression of PSF or decreasing expression of VL30-1 RNA suppresses cell proliferation in culture and tumorigenesis in mice; and (iii) decreasing expression of PSF or increasing expression of VL30-1 RNA promotes cell proliferation in culture and tumorigenesis in mice. These results indicate that PSF is a major tumor-suppressor protein and VL30-1 RNA is a major tumor-promoter RNA in mice. Although VL30-1 RNA can integrate into the cell genome, tumor promotion by VL30-1 RNA involves a trans effect rather than a cis effect on gene transcription. Expression of VL30-1 RNA is 5- to 8-fold higher in mouse tumor lines than in mouse fibroblast or myoblast lines, whereas expression of PSF mRNA does not decrease in the tumor lines, suggesting that tumorigenesis is driven by an increase of VL30-1 RNA rather than a decrease of PSF. A similar regulatory mechanism functions in human cells, except that human PSF-binding RNAs replace VL30-1 RNA, which is not encoded in the human genome. We propose that PSF protein and PSF-binding RNAs have a central role in the reversible regulation of mammalian cell proliferation and tumorigenesis and that increasing PSF expression or decreasing PSF-binding RNA expression in tumor cells is a potential therapeutic strategy for cancer.
Related studies showed that the protein PSF represses proto-oncogene transcription, and VL30-1 RNA, a mouse noncoding retroelement RNA, binds and releases PSF from a proto-oncogene, activating transcription. Here we show that this mechanism regulates tumorigenesis in human cells, with human RNAs replacing VL30-1 RNA. A library of human RNA fragments was used to isolate, by affinity chromatography, 5 noncoding RNA fragments that bind to human PSF (hPSF), releasing hPSF from a proto-oncogene and activating transcription. Each of the 5 RNA fragments maps to a different human gene. The tumorigenic function of the hPSF-binding RNAs was tested in a human melanoma line and mouse fibroblast line, by determining the effect of the RNAs on formation of colonies in agar and tumors in mice. (i) Expressing in human melanoma cells the RNA fragments individually promoted tumorigenicity. (ii) Expressing in human melanoma cells a shRNA, which causes degradation of the endogenous RNA from which an RNA fragment was derived, suppressed tumorigenicity. (iii) Expressing in mouse NIH/3T3 cells the RNA fragments individually resulted in transformation to tumorigenic cells. (iv) A screen of 9 human tumor lines showed that each line expresses high levels of several hPSF-binding RNAs, relative to the levels in human fibroblast cells. We conclude that human hPSF-binding RNAs drive transformation and tumorigenesis by reversing PSF-mediated repression of proto-oncogene transcription and that dysfunctional regulation of human hPSF-binding RNA expression has a central role in the etiology of human cancer.