Gene Summary

Gene:SNCG; synuclein gamma
Aliases: SR, BCSG1
Summary:This gene encodes a member of the synuclein family of proteins which are believed to be involved in the pathogenesis of neurodegenerative diseases. Mutations in this gene have also been associated with breast tumor development. [provided by RefSeq, Jan 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (10)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Colorectal Cancer
  • Receptors, Progesterone
  • Stress, Physiological
  • Azacitidine
  • Down-Regulation
  • CpG Islands
  • Apoptosis
  • Lymphatic Metastasis
  • Base Sequence
  • Neoplasm Metastasis
  • Immunohistochemistry
  • Gene Expression
  • Molecular Sequence Data
  • Nerve Tissue Proteins
  • Estrogen Receptors
  • Receptor, erbB-2
  • Gene Silencing
  • Cancer Gene Expression Regulation
  • DNA Methylation
  • Disease-Free Survival
  • Cell Proliferation
  • Carcinoma
  • Synucleins
  • Disease Progression
  • Chromosome 10
  • Signal Transduction
  • Polymerase Chain Reaction
  • Messenger RNA
  • Transcriptional Activation
  • Staging
  • siRNA
  • tau Proteins
  • Transfection
  • Neoplasm Proteins
  • Biomarkers, Tumor
  • Cell Movement
  • Ovarian Cancer
  • Breast Cancer
  • Exons
  • Promoter Regions
Tag cloud generated 31 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).

Latest Publications: SNCG (cancer-related)

Zhang C, Gu L, Li X, Wang J
Silencing of
Cell Mol Biol Lett. 2019; 24:49 [PubMed] Free Access to Full Article Related Publications

Samec M, Liskova A, Kubatka P, et al.
The role of dietary phytochemicals in the carcinogenesis via the modulation of miRNA expression.
J Cancer Res Clin Oncol. 2019; 145(7):1665-1679 [PubMed] Related Publications
PURPOSE: Phytochemicals are naturally occurring plant-derived compounds and some of them have the potential to serve as anticancer drugs. Based on recent evidence, aberrantly regulated expression of microRNAs (miRNAs) is closely associated with malignancy. MicroRNAs are characterized as small non-coding RNAs functioning as posttranscriptional regulators of gene expression. Accordingly, miRNAs regulate various target genes, some of which are involved in the process of carcinogenesis.
RESULTS: This comprehensive review emphasizes the anticancer potential of phytochemicals, either isolated or in combination, mediated by miRNAs. The ability to modulate the expression of miRNAs demonstrates their importance as regulators of tumorigenesis. Phytochemicals as anticancer agents targeting miRNAs are widely studied in preclinical in vitro and in vivo research. Unfortunately, their anticancer efficacy in targeting miRNAs is less investigated in clinical research.
CONCLUSIONS: Significant anticancer properties of phytochemicals as regulators of miRNA expression have been proven, but more studies investigating their clinical relevance are needed.

Kapinova A, Kubatka P, Liskova A, et al.
Controlling metastatic cancer: the role of phytochemicals in cell signaling.
J Cancer Res Clin Oncol. 2019; 145(5):1087-1109 [PubMed] Related Publications
PURPOSE: Cancer is a serious health issue and a leading cause of death worldwide. Most of the cancer patients (approximately 90%) do not die from the consequences of the primary tumor development, but due to a heavily treatable metastatic invasion. During the lengthy multistep process of carcinogenesis, there are a lot of opportunities available to reverse or slow down the tissue invasion or the process of tumor metastasis formation.
RESULTS: Current research has brought many promising results from anti-metastatic experimental studies, and has shown that chemoprevention by natural or semisynthetic phytochemicals with plethora of biological activities could be one of the potentially effective options in the fight against this problem. However, there is a lack of clinical trials to confirm these findings. In this review, we focused on summarization and discussion of the general features of metastatic cancer, and recent preclinical and clinical studies dealing with anti-metastatic potential of various plant-derived compounds.
CONCLUSIONS: Based on our findings, we can conclude and confirm our hypothesis that phytochemicals with pleiotropic anticancer effects can be very useful in retarding and/or reversing the metastasis process, and can also be used to prevent tissue invasion and metastases. But, further studies in this area are certainly necessary and desirable.

Kinslechner K, Schütz B, Pistek M, et al.
Loss of SR-BI Down-Regulates MITF and Suppresses Extracellular Vesicle Release in Human Melanoma.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Melanoma is a skin tumor with a high tendency for metastasis and thus is one of the deadliest cancers worldwide. Here, we investigated the expression of the scavenger receptor class B type 1 (SR-BI), a high-density lipoprotein (HDL) receptor, and tested for its role in melanoma pigmentation as well as extracellular vesicle release. We first analyzed the expression of

Wang R, Zhang J, Wang S, et al.
The Cardiotoxicity Induced by Arsenic Trioxide is Alleviated by Salvianolic Acid A via Maintaining Calcium Homeostasis and Inhibiting Endoplasmic Reticulum Stress.
Molecules. 2019; 24(3) [PubMed] Free Access to Full Article Related Publications
Arsenic trioxide (ATO) has been verified as a breakthrough with respect to the management of acute promyelocytic leukemia (APL) in recent decades but associated with some serious adverse phenomena, particularly cardiac functional abnormalities. Salvianolic acid A (Sal A) is a major effective component in treating ATO-induced cardiotoxicity. Therefore, the objective of our study was to assess whether Sal A had protective effects by the regulation of calcium homeostasis and endoplasmic reticulum (ER) stress. For the in vivo study, BALB/c mice were treated with ATO and/or Sal A via daily tail vein injections for two weeks. For the in vitro study, we detected the effects of ATO and/or Sal A in real time using adult rat ventricular myocytes (ARVMs) and an IonOptix MyoCam system. Our results showed that Sal A pretreatment alleviated cardiac dysfunction and Ca

Vanova B, Kalman M, Jasek K, et al.
Droplet digital PCR revealed high concordance between primary tumors and lymph node metastases in multiplex screening of KRAS mutations in colorectal cancer.
Clin Exp Med. 2019; 19(2):219-224 [PubMed] Related Publications
The proto-oncogene KRAS belongs among the most frequently mutated genes in all types of cancer and is also very important oncogene related to colorectal tumors. The detection of mutations in this gene in primary tumor is a predictive biomarker for the anti-EGFR therapy in metastatic CRC (mCRC); however, the patients with wild-type KRAS can also show resistance to the personalized medicine. The droplet-based digital PCR technology has improved the analytical sensitivity of the mutations detection, which led us to the idea about the optimization of this approach for KRAS testing. In this study, we report the application of ddPCR technology in order to analyze the presence of KRAS mutations in primary tumor and matched metastasis in lymph nodes (LNs) from patients with mCRC and address the question, whether the improvement in the detection method can lower the discrepancies of KRAS mutations detection between the primary tumor and regional LNs. Genomic DNA with wtKRAS and commercial DNA with mtKRAS (G12D) were used to set up the ddPCR reaction. Formalin-fixed paraffin-embedded tissues from primary tumor and positive lymph node from 31 patients with mCRC were analyzed using ddPCR and Sanger sequencing. KRAS status of primary tumors was known; however, the mutation status of lymph nodes was not detected previously. From 31 samples of primary tumors, our results corresponded to results from IVD kit in 30 cases. For one patient, ddPCR detected KRAS mutation in comparison with negative result of the IVD kit. In the samples of metastatic infiltrated LNs, ddPCR detected 16 samples as a WT KRAS and 15 lymph nodes showed positivity for KRAS mutation, whereby Sanger sequencing found KRAS mutations in 8 cases only. We also found two cases where genetic conditions of KRAS gene differed between primary tumor and infiltrated lymph node, both "low-grade" adenocarcinoma. Our study approved that ddPCR method is adequate technique with high sensitivity and in the future may be used as a diagnostic tool for evaluation of KRAS mutations, especially in infiltrated LNs of patients with mCRC.

Kovalska J, Cervinkova M, Chmelikova E, et al.
Immunohistochemical Evidence of the Involvement of Natural Killer (CD161
In Vivo. 2019 Jan-Feb; 33(1):47-52 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: Spontaneous regression (SR) of tumours is a rare phenomenon not yet fully understood. The aim of this study was to investigate immune cells infiltrating progressive and SR tumours in a Lewis rat sarcoma model.
MATERIALS AND METHODS: Rats were subcutaneously inoculated with rat sarcoma R5-28 (clone C4) cells. Developing tumours were obtained on day 42 and cryosections were immunohistochemically processed for detection of immune cells.
RESULTS: A high density of granulocytes was found in the necrotic areas of both progressive and SR tumours. CD4
CONCLUSION: Based on the differences in number and distribution of the immune cell subpopulations, we believe that natural killer (CD161

Kašubová I, Holubeková V, Janíková K, et al.
Next Generation Sequencing in Molecular Diagnosis of Lynch Syndrome - a Pilot Study Using New Stratification Criteria.
Acta Medica (Hradec Kralove). 2018; 61(3):98-102 [PubMed] Related Publications
The development of the new technologies such as the next-generation sequencing (NGS) makes more accessible the diagnosis of genetically heterogeneous diseases such as Lynch syndrome (LS). LS is one of the most common hereditary form of colorectal cancer. This autosomal dominant inherited disorder is caused by deleterious germline mutations in one of the mismatch repair (MMR) genes - MLH1, MSH2, MSH6 or PMS2, or the deletion in the EPCAM gene. These mutations eventually result in microsatellite instability (MSI), which can be easily tested in tumor tissue. According to the actual recommendations, all patients with CRC that are suspect to have LS, should be offered the MSI testing. When the MSI is positive, these patients should be recommended to genetic counseling. Here we report a pilot study about the application of NGS in the LS diagnosis in patients considered to have sporadic colorectal cancer. The inclusion criteria for the NGS testing were MSI positivity, BRAF V600E and MHL1 methylation negativity. We have used 5 gene amplicon based massive parallel sequencing on MiSeq platform. In one patient, we have identified a new pathogenic mutation in the exon 4 of the MSH6 gene that was previously not described in ClinVar, Human Gene Mutation Database, Ensembl and InSight databases. This mutation was confirmed by the Sanger method. We have shown that the implementation of new criteria for colorectal patients screening are important in clinical praxis and the NGS gene panel testing is suitable for routine laboratory settings.

Romero-Gavilán F, Araújo-Gomes N, García-Arnáez I, et al.
The effect of strontium incorporation into sol-gel biomaterials on their protein adsorption and cell interactions.
Colloids Surf B Biointerfaces. 2019; 174:9-16 [PubMed] Related Publications
It is known strontium can both inhibit the osteoclast formation and stimulate the osteoblast maturation, so biomaterials containing this element can favour bone structure stabilisation. The addition of Sr to biomaterials could affect their interactions with proteins and cells. Here, a silica-hybrid sol-gel network doped with different amounts of SrCl

Chovanec M, Cierna Z, Miskovska V, et al.
βcatenin is a marker of poor clinical characteristics and suppressed immune infiltration in testicular germ cell tumors.
BMC Cancer. 2018; 18(1):1062 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: WNT/βcatenin (WNTβ) pathway is activated in early stages of embryonic development. We aimed to evaluate the significance of βcatenin in germ cell tumors (GCTs) and explore associations with the inflamed environment.
METHODS: Surgical specimens from 247 patients were analyzed. Βcatenin expression was detected in the tumor tissue by immunohistochemistry and correlated with clinical characteristics, outcome, PD-L1 expression and systemic immune-inflammation index (SII). The Ingenuity Pathway Analysis (IPA) was used to investigate the immune-cell related effects of βcatenin and PD-L1 encoding genes.
RESULTS: βcatenin was expressed in 86.2% of GCTs. The expression in seminomas was significantly lower compared to all subtypes of non-seminoma (all P <  0.0001). A high expression (weighted histoscore > 150) was associated with primary mediastinal non-seminoma (P = 0.035), intermediate/poor risk disease (P = 0.033) and high tumor markers (P = 0.035). We observed a positive correlation with the PD-L1 in tumor and an inverse correlation with the SII. IPA uncovered relationships of CTNNB (βcatenin) and CD274 (PD-L1) genes and their effects on differentiation, proliferation and activation of lymphocyte subtypes.
CONCLUSION: Herein, we showed that βcatenin is associated with male adult GCT characteristics as well as supressed immune environment.

Lord RM, Zegke M, Henderson IR, et al.
β-Ketoiminato Iridium(III) Organometallic Complexes: Selective Cytotoxicity towards Colorectal Cancer Cells HCT116 p53-/.
Chemistry. 2019; 25(2):495-500 [PubMed] Related Publications
This report presents a new library of organometallic iridium(III) compounds of the type [Cp*IrCl(L)] (Cp*=pentamethylcyclopentadienyl and L=a functionalized β-ketoiminato ligand) showing moderate to high cytotoxicity against a range of cancer cell lines. All compounds show increased activity towards colorectal cancer, with preferential activity observed against the immortalized p53-null colorectal cell line, HCT116 p53-/-, with sensitivity factors (SF) up to 26.7. Additionally, the compounds have excellent selectivity for cancerous cells when tested against normal cell types, with selectivity ratios (SR) up to 35.6, contrary to that of cisplatin, which is neither selective nor specific for cancerous cells (SF=0.43 and SR=0.7-2.3). This work provides a preliminary understanding of the cytotoxicity of iridium compounds in the absence of p53 and has potential applications in treatment of cancers for which the p53 gene is absent or mutant.

Truong TH, Lange CA
Deciphering Steroid Receptor Crosstalk in Hormone-Driven Cancers.
Endocrinology. 2018; 159(12):3897-3907 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Steroid hormone receptors (SRs) have a multitude of functions in human biology and disease progression. The SR family of related ligand-activated transcription factors includes androgen, estrogen, glucocorticoid, mineralocorticoid, and progesterone receptors. Antiestrogen or estrogen receptor (ER)-targeted therapies to block ER action remain the primary treatment of luminal breast cancers. Although this strategy is successful, ∼40% of patients eventually relapse due to endocrine resistance. The majority of hormone-independent tumors retain some level of SR expression, but sidestep hormone ablation treatments. SRs are known to crosstalk extensively with kinase signaling pathways, and this interplay has been shown to bypass ER-targeted therapies in part by providing alternative proliferation and survival signals that enable hormone independence. Modified receptors adopt alternate conformations that resist antagonism or promote agonism. SR-regulated transcription and SR-binding events have been classically studied as single receptor events using single hormones. However, it is becoming increasingly evident that individual steroids and SRs rarely act alone. Emerging evidence shows that coexpressed SRs crosstalk with each other in hormone-driven cancers, such as breast and prostate. Crosstalk between related SRs allows them to modulate signaling and transcriptional responses to noncognate ligands. This flexibility can lead to altered genomic binding and subsequent changes in SR target gene expression. This review will discuss recent mechanistic advances in elucidating SR crosstalk and the implications for treating hormone-driven cancers. Understanding this crosstalk (i.e., both opposing and collaborative) is a critical step toward expanding and modernizing endocrine therapies and will ultimately improve patient outcomes.

Gopalakrishnan V, Dahal S, Radha G, et al.
Characterization of DNA double-strand break repair pathways in diffuse large B cell lymphoma.
Mol Carcinog. 2019; 58(2):219-233 [PubMed] Related Publications
Efficient DNA repair is indispensable for maintaining genomic integrity in humans. Cancer associated deletions and mutations are mainly due to misrepaired DNA double-strand breaks (DSBs). Classical nonhomologous end joining (c-NHEJ) and homologous recombination (HR) are two major DSB repair pathways in humans. An error prone, alternative NHEJ pathway that utilizes microhomology was also reported in cancer cells and to a lesser extent in normal cells. In the present study, we evaluated the efficiency of various DSB repair pathways in the most common lymphoma, the diffuse large B cell lymphoma (DLBCL). Here we show that DNA repair through c-NHEJ pathway is limited in SUDHL8, a cell line derived from a DLBCL patient. Unlike c-NHEJ, microhomology mediated end joining (MMEJ) was predominant at physiological temperature. Consistent with the observation, expression level of repair proteins such as LIGASE I, LIGASE III, PARP1, CtIP, and MRE11 was higher in DLBCL cells when compared to c-NHEJ proteins. Further, inhibition of LIGASE I or MRE11, led to reduction in the efficiency of MMEJ in DLBCL cells. Besides, HR-mediated DSB repair occurring through gene conversion was observed. Thus, our results reveal the predominance of MMEJ over c-NHEJ in repairing DSBs in DLBCL cells, while error-free repair through HR was also evident.

Kuranaga Y, Sugito N, Shinohara H, et al.
SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells.
Int J Mol Sci. 2018; 19(10) [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Serine and arginine rich splicing factor 3 (SRSF3), an SR-rich family protein, has an oncogenic function in various kinds of cancer. However, the detailed mechanism of the function had not been previously clarified. Here, we showed that the SRSF3 splicer regulated the expression profile of the pyruvate kinase, which is one of the rate-limiting enzymes in glycolysis. Most cancer cells express pyruvate kinase muscle 2 (PKM2) dominantly to maintain a glycolysis-dominant energy metabolism. Overexpression of SRSF3, as well as that of another splicer, polypyrimidine tract binding protein 1 (PTBP1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), in clinical cancer samples supported the notion that these proteins decreased the Pyruvate kinase muscle 1 (PKM1)/PKM2 ratio, which positively contributed to a glycolysis-dominant metabolism. The silencing of

Kalinkova L, Zmetakova I, Smolkova B, et al.
Decreased methylation in the SNAI2 and ADAM23 genes associated with de-differentiation and haematogenous dissemination in breast cancers.
BMC Cancer. 2018; 18(1):875 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: In breast cancer (BC), deregulation of DNA methylation leads to aberrant expressions and functions of key regulatory genes. In our study, we investigated the relationship between the methylation profiles of genes associated with cancer invasivity and clinico-pathological parameters. In detail, we studied differences in the methylation levels between BC patients with haematogenous and lymphogenous cancer dissemination.
METHODS: We analysed samples of primary tumours (PTs), lymph node metastases (LNMs) and peripheral blood cells (PBCs) from 59 patients with sporadic disseminated BC. Evaluation of the DNA methylation levels of six genes related to invasivity, ADAM23, uPA, CXCL12, TWIST1, SNAI1 and SNAI2, was performed by pyrosequencing.
RESULTS: Among the cancer-specific methylated genes, we found lower methylation levels of the SNAI2 gene in histologic grade 3 tumours (OR = 0.61; 95% CI, 0.39-0.97; P = 0.038) than in fully or moderately differentiated cancers. We also evaluated the methylation profiles in patients with different cancer cell dissemination statuses (positivity for circulating tumour cells (CTCs) and/or LNMs). We detected the significant association between reduced DNA methylation of ADAM23 in PTs and presence of CTCs in the peripheral blood of patients (OR = 0.45; 95% CI, 0.23-0.90; P = 0.023).
CONCLUSION: The relationships between the decreased methylation levels of the SNAI2 and ADAM23 genes and cancer de-differentiation and haematogenous dissemination, respectively, indicate novel functions of those genes in the invasive processes. After experimental validation of the association between the lower values of SNAI2 and ADAM23 methylation and clinical features of aggressive BCs, these methylation profiles could improve the management of metastatic disease.

Kim T, Moon JH, Ahn JS, et al.
Next-generation sequencing-based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse.
Blood. 2018; 132(15):1604-1613 [PubMed] Related Publications
Next-generation sequencing (NGS) has been applied to define clinically relevant somatic mutations and classify subtypes in acute myeloid leukemia (AML). Persistent allelic burden after chemotherapy is associated with higher relapse incidence, but presence of allelic burden in AML patients after receiving allogeneic hematopoietic cell transplantation (HCT) has not been examined longitudinally. As such, we aimed to assess the feasibility of NGS in monitoring AML patients receiving HCT. Using a targeted gene panel, we performed NGS in 104 AML patients receiving HCT using samples collected at diagnosis, pre-HCT, and post-HCT at day 21 (post-HCT

Deshpande RP, Panigrahi M, Y B V K C, Babu PP
Profiling of microRNAs modulating cytomegalovirus infection in astrocytoma patients.
Neurol Sci. 2018; 39(11):1895-1902 [PubMed] Related Publications
Astrocytoma is recognized as the most common neoplasm of the brain with aggressive progression. The therapeutic regime for glioblastoma, the most aggressive astrocytoma, often consists of aggressive chemo and radiotherapy. The present holistic approaches, however, have failed to influence the quality life of patients. Therefore, it is necessary to understand the underlying mechanisms of its progression for updated therapeutic evaluation. Human cytomegalovirus (HCMV) is reported to be associated with glioblastoma progression. The hypothesis still remains controversial due to the lack of concrete evidences. Here, we report the profile of miRNAs encoded by human host and the cytomegalovirus (CMV) involved in modulation of CMV infection in surgically resected human astrocytoma tissue samples of various malignancy grades (n = 24). Total RNA from the control brain and tumor tissues was extracted by TriZol reagent. The expression levels of the mature form of miRNA were detected by real-time PCR. Primarily, we found the upregulation of miR-210-3p, miR-155-5p, miR-UL-112-3p, miR-183-5p, and miR-223-5p in high-grade astrocytic tumors as compared with low-grade tumor tissues. miR-214-3p is significantly expressed in control brain tissues and its expression decreased with astrocytoma grade progression. This miRNA was reported to be associated with antiviral proprieties. Among CMV-encoded miRNA, miR-UL-112-3p was significantly upregulated in glioblastoma tissue samples and may be involved in providing immune escape to the virus as well as involved in modulating the immune microenvironment of glioblastoma. Taken together, we conclude the possible involvement of miRNAs in modulating the CMV dependent astrocytoma progression.

Naveen Kumar M, Babu RL, Patil RH, et al.
Protein kinases orchestrate cell cycle regulators in differentiating BeWo choriocarcinoma cells.
Mol Cell Biochem. 2019; 452(1-2):1-15 [PubMed] Related Publications
Choriocarcinoma, a trophoblastic neoplasia, occurs in women as an incidence of abnormal pregnancy. BeWo choriocarcinoma cells derived from the abnormal placentation are a suitable model system to study the factors associated with differentiation, invasion and other cellular events as an alternative to clinical samples. Many protein kinases orchestrate the complex events of cell cycle and in case of malignancy such regulators are found to be mutated. In the present study, BeWo cells treated with forskolin (Fo) and phorbol 12-myristate 13-acetate (PMA) were used to study the role of PKA (protein kinase A) and PKC (protein kinase C), respectively, on the expression pattern of differentiation-related genes, membrane markers, PKC isoforms and cell cycle regulators. The effect of Fo and PMA on the cell proliferation was assessed. Progressive induction of alkaline phosphatase level and formation of multinucleated differentiated cells were observed in the cells treated with Fo. Exposure of cells to Fo and PMA induced the mRNA transcripts of α-hCG, β-hCG and endoglin and down-regulates E-cadherin at mRNA and protein levels. Synergistic levels of both up- and down-regulated genes/proteins were observed when cells were treated with the combination of Fo and PMA. The mRNA levels of cyclin D1, cyclin E1, p21, Rb, p53, caspase-3 and caspase-8 decreased gradually during differentiation. Fo significantly inhibited the protein levels of PCNA, Rb, PKC-α and PMA stimulated mRNA expression of PKC-ε and PKC-δ. Further, failure in the activation of essential components of the cell cycle machinery caused G2/M phase arrest in differentiating BeWo cells.

Su Z, Song J, Wang Z, et al.
Tumor promoter TPA activates Wnt/β-catenin signaling in a casein kinase 1-dependent manner.
Proc Natl Acad Sci U S A. 2018; 115(32):E7522-E7531 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The tumor promoter 12-

Roberts KG, Reshmi SC, Harvey RC, et al.
Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children's Oncology Group.
Blood. 2018; 132(8):815-824 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL;

Rea K, Roggiani F, De Cecco L, et al.
Simultaneous E-cadherin and PLEKHA7 expression negatively affects E-cadherin/EGFR mediated ovarian cancer cell growth.
J Exp Clin Cancer Res. 2018; 37(1):146 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: The disruption of E-cadherin-mediated adhesion is considered an important driver of tumor progression. Nevertheless, numerous studies have demonstrated that E-cadherin promotes growth- or invasion-related signaling, contrary to the prevailing notion. During tumor progression, epithelial ovarian cancer (EOC) maintains E-cadherin expression and can positively affect EOC cell growth by contributing to PI3K/AKT activation. In polarized epithelia PLEKHA7, a regulator of the zonula adherens integrity, impinges E-cadherin functionality, but its role in EOCs has been never studied.
METHODS: Ex-vivo EOC cells and cell lines were used to study E-cadherin contribution to growth and EGFR activation. The expression of the proteins involved was assessed by real time RT-PCR, immunohistochemistry and western blotting. Cells growth and drug susceptibility was monitored in different 3-dimensional (3D) systems. Recombinant lentivirus-mediated gene expression, western blotting, immunoprecipitation and confocal microscopy were applied to investigate the biological impact of PLEKHA7 on E-cadherin behaviour. The clinical impact of PLEKHA7 was determined in publicly available datasets.
RESULTS: We show that E-cadherin expression contributes to growth of EOC cells and forms a complex with EGFR thus positively affecting ligand-dependent EGFR/CDK5 signaling. Accordingly, 3D cultures of E-cadherin-expressing EOC cells are sensitive to the CDK5 inhibitor roscovitine combined with cisplatin. We determined that PLEKHA7 overexpression reduces the formation of E-cadherin-EGFR complex, EGFR activation and cell tumorigenicity. Clinically, PLEKHA7 mRNA is statistically decreased in high grade EOCs respect to low malignant potential and low grade EOCs and correlates with better EOC patient outcome.
CONCLUSIONS: These data represent a significant step towards untangling the role of E-cadherin in EOCs by assessing its positive effects on EGFR/CDK5 signaling and its contribution to cell growth. Hence, the inhibition of this signaling using a CDK5 inhibitor exerts a synergistic effect with cisplatin prompting on the design of new therapeutic strategies to inhibit growth of EOC cells. We assessed for the first time in EOC cells that PLEKHA7 induces changes in the asset of E-cadherin-containing cell-cell contacts thus inhibiting E-cadherin/EGFR crosstalk and leading to a less aggressive tumor phenotype. Accordingly, PLEKHA7 levels are lower in high grade EOC patient tumors and EOC patients with better outcomes display higher PLEKHA7 levels.

Fan C, Liu J, Tian J, et al.
siRNA Targeting of the SNCG Gene Inhibits the Growth of Gastric Carcinoma SGC7901 Cells in vitro and in vivo by Downregulating the Phosphorylation of AKT/ERK.
Cytogenet Genome Res. 2018; 154(4):209-216 [PubMed] Related Publications
The aim of the study was to evaluate the effects of synuclein-γ (SNCG) silencing on gastric cancer SGC7901 cells and to elucidate the associated mechanisms. pGCSIL-lentiviral siRNA targeting of the SNCG gene was employed to inhibit SNCG expression. Several experiments such as quantitative real-time PCR, Western blotting, MTT, colony formation, migration assay, and flow cytometry were performed to investigate the biological behavior of infected SGC7901 cells. BALB/c nude mice were used as tumor xenograft models to assess the effects of SNCG silencing on tumor growth. Western blot analysis was carried out to determine the relative levels of AKT, p-AKT, ERK, and p-ERK expression. Our results showed that SNCG was overexpressed in SGC7901 cells as compared to normal gastric mucosal epithelial cells. SGC7901 cells transfected with SNCG siRNA demonstrated significantly decreased gastric cancer growth (p < 0.01), reduced cell migration, cell cycle arrest in the G0/G1 phase, promoted tumor cell apoptosis (p < 0.01), and inhibited tumorigenesis in xenograft animal models. Western blot analysis indicated that the protein levels of p-AKT and p-ERK were much lower in the SNCG siRNA group than in the control groups. The results of the present study suggest that SNCG siRNA plays a significant role in the proliferation, migration, and tumorigenesis of gastric cancer by downregulating the phosphorylation of AKT and ERK. RNA interference-mediated silencing of SNCG may provide an opportunity to develop a novel treatment strategy for gastric cancer.

Li M, Su Y, Zhang F, et al.
A dual-targeting reconstituted high density lipoprotein leveraging the synergy of sorafenib and antimiRNA21 for enhanced hepatocellular carcinoma therapy.
Acta Biomater. 2018; 75:413-426 [PubMed] Related Publications
Sorafenib (So) is a multi-target kinase inhibitor extensively used in clinic for hepatocellular carcinoma therapy. It demonstrated strong inhibition both in tumor proliferation and tumor angiogenesis, while hampered by associated cutaneous side-effect and drug resistance. The knockdown of miR-21 with antisense oligonucleotides (antimiRNA21) was regarded as an efficient strategy for increasing tumor sensibility to chemotherapy, which could be employed to appreciate the efficacy of So. Herein, we successfully formulated a dual-targeting delivery system for enhanced hepatocellular carcinoma therapy by encapsulating So and antimiRNA21 in RGD pentapeptide-modified reconstituted high-density lipoprotein (RGD-rHDL/So/antimiRNA21). The RGD and apolipoprotein A-I (ApoA-I) on nanoparticles (NPs) could drive the system simultaneously to tumor neovascular and parenchyma by binding to the overexpressed ανβ3-integrin and SR-B1 receptors, achieving precise delivery of therapeutics to maximize the efficacy. A series in vitro and in vivo experiments revealed that co-delivery of So and antimiRNA21 by RGD-rHDL significantly strengthened the anti-tumor and anti-angiogenic effect of So with negligible toxicity towards major organs, reversed drug-resistance and was capable of remodeling tumor environments. The constructed RGD-rHDL/So/antimiRNA21 with improved efficacy and excellent tumor targeting ability provided new idea for chemo-gene combined therapy in hepatocellular carcinoma.
STATEMENT OF SIGNIFICANCE: Sorafenib (So) is a multi-target kinase inhibitor which was approved by FDA as first-line drug for hepatocellular carcinoma (HCC) therapy. However, long term application of So in clinic was hampered by serious dermal toxicity and drug resistance. Although numerous researchers were devoted to finding alternatives or therapies as combination treatments with So to reach more desired therapeutic efficacy, the therapeutic options were still limited. The present study prepares RGD pentapeptide decorated biomimic reconstituted high-density lipoprotein (rHDL) loaded with So and antimiRNA21 (RGD-rHDL/So/antimiRNA21) for enhanced HCC therapy. The RGD-rHDL/So/antimiRNA21 NPs offer an effective platform for anti-tumor and anti-angiogenesis therapy in HCC and provide new approach to reverse drug-resistance of So for feasible clinical application.

Liang Y, Tebaldi T, Rejeski K, et al.
SRSF2 mutations drive oncogenesis by activating a global program of aberrant alternative splicing in hematopoietic cells.
Leukemia. 2018; 32(12):2659-2671 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Recurrent mutations in the splicing factor SRSF2 are associated with poor clinical outcomes in myelodysplastic syndromes (MDS). Their high frequency suggests these mutations drive oncogenesis, yet the molecular explanation for this process is unclear. SRSF2 mutations could directly affect pre-mRNA splicing of a vital gene product; alternatively, a whole network of gene products could be affected. Here we determine how SRSF2 mutations globally affect RNA binding and splicing in vivo using HITS-CLIP. Remarkably, the majority of differential binding events do not translate into alternative splicing of exons with SRSF2

Yang S, Jia R, Bian Z
SRSF5 functions as a novel oncogenic splicing factor and is upregulated by oncogene SRSF3 in oral squamous cell carcinoma.
Biochim Biophys Acta Mol Cell Res. 2018; 1865(9):1161-1172 [PubMed] Related Publications
Alternative splicing of precursor messenger RNA has been increasingly associated with tumorigenesis. The serine/arginine-rich protein (SR) family plays key roles in the regulation of pre-mRNA alternative splicing. Increasing evidence has demonstrated that the SR protein family is involved in tumorigenesis. However, the functions and mechanisms of SR proteins in tumourigenesis remain largely unknown. In the present study, we discovered that serine/arginine-rich splicing factor 5 (SRSF5) is a novel oncogenic splicing factor that is overexpressed in oral squamous cell carcinoma (OSCC) tissues and cells, being crucial for OSCC cell proliferation and tumor formation. Overexpression of SRSF5 transformed immortal rodent fibroblasts to form tumors in nude mice, while downregulation of SRSF5 in oral squamous cell lines retarded cell growth, cell cycle progression, and tumor growth. The expression of SRSF5 is controlled by an autoregulation mechanism. Serine/arginine-rich splicing factor 3 (SRSF3) has been identified as an oncogene. We found that SRSF5 is a novel target of SRSF3. SRSF3 impairs the autoregulation of SRSF5 and promotes SRSF5 overexpression in cancer cells. Altogether, the present study demonstrated that SRSF5 is a novel oncogene that is upregulated by SRSF3 in OSCC cells.

Norelli M, Camisa B, Barbiera G, et al.
Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells.
Nat Med. 2018; 24(6):739-748 [PubMed] Related Publications
In the clinic, chimeric antigen receptor-modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell-mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies.

Adamopoulos PG, Raptis GD, Kontos CK, Scorilas A
Discovery and expression analysis of novel transcripts of the human SR-related CTD-associated factor 1 (SCAF1) gene in human cancer cells using Next-Generation Sequencing.
Gene. 2018; 670:155-165 [PubMed] Related Publications
The human SR-related CTD associated factor 1 (SCAF1) gene is a new member of the human SR (Ser/Arg-rich) superfamily of pre-mRNA splicing factors, which has been discovered and cloned by members of our lab. SCAF1 interacts with the CTD domain of the RNA polymerase II polypeptide A and is firmly involved in pre-mRNA splicing. Although it was found to be expressed widely in multiple human tissues, its mRNA levels vary a lot. The significant relation of SCAF1 with cancer has been confirmed by many studies, since SCAF1 mRNA transcript was found to be overexpressed in breast and ovarian tumors, confirming its significant prognostic value as a cancer biomarker in both these human malignancies. In this study, we describe the discovery and cloning of fifteen novel transcripts of the human SCAF1 gene (SCAF1 v.2 - v.16), using nested PCR and NGS technology. In detail, extensive bioinformatic analysis revealed that these novel SCAF1 splice variants comprise a total of nine novel alternative splicing events between the annotated exons of the gene, thus producing seven novel SCAF1 transcripts with open-reading frames, which are predicted to encode novel SCAF1 isoforms and eight novel SCAF1 transcripts with premature termination codons that are likely long non-coding RNAs. Additionally, a novel 3' UTR was discovered and cloned using nested 3' RACE and was validated with Sanger sequencing. In order to validate the NGS findings as well as to investigate the expression profile of each novel transcript, RT-PCR experiments were carried out with the use of variant-specific primers. Since SCAF1 is implicated in many human malignancies, qualifying as a potential biomarker, the quantification of the presented novel transcripts in human samples may have clinical applications in different types of cancer.

Li J, Gao W, Yu B, et al.
Multi-slice spiral CT evaluation of breast cancer chemotherapy and correlation between CT results and breast cancerspecific gene 1.
J BUON. 2018 Mar-Apr; 23(2):378-383 [PubMed] Related Publications
PURPOSE: To investigate multi-slice spiral CT (MSCT) imaging with breast cancer chemotherapy and the correlation between MSCT and breast cancer-specific gene 1 (BCSG1).
METHODS: 86 patients with breast cancer were enrolled from January 2016 to May 2017. All of them were treated with neoadjuvant chemotherapy, and underwent MSCT scan before and after treatment to evaluate the efficacy of chemotherapy. The expression of BCSG1 in tumor tissue was detected by immunohistochemistry and the correlation between CT results and BCSG1 was analyzed.
RESULTS: MSCT evaluation of the efficacy of chemotherapy in breast cancer patients was consistent with pathological evaluation (p<0.05). MSCT in patients after chemotherapy was significantly better than before chemotherapy (p<0.05). CT examination showed that tumor diameter and lymph node size were significantly reduced after chemotherapy (p<0.05). The positive rates of BCSG1 in patients with different TNM stages after chemotherapy were significantly decreased (p<0.05) and the CT perfusion value of BCSG1 in the low expression group was significantly higher than in the high expression group (p<0.05).
CONCLUSIONS: MSCT can accurately evaluate the effect of chemotherapy in breast cancer. The results of MSCT were closely related to the expression of BCSG1, which may provide a reference for predicting the effect of chemotherapy in breast cancer which could have important clinical significance.

Kong YH, Xu SP
Salidroside prevents skin carcinogenesis induced by DMBA/TPA in a mouse model through suppression of inflammation and promotion of apoptosis.
Oncol Rep. 2018; 39(6):2513-2526 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Salidroside (SR) is a main component of Rhodiola rosea L. and exhibits a variety of pharmacologic properties. The present study was carried out to explore the potential effect of SR against skin cancer induced by 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13‑acetate (TPA) in female Institute for Cancer Research (ICR) mice and to reveal the underlying molecular targets regulated by SR. The mice were randomly divided into 4 groups: control, DMBA/TPA, DMBA/TPA+SR (20 mg/kg) and DMBA/TPA+SR (40 mg/kg). SR was administered to mice five times a week after DMBA treatments. In our study, we found that SR dose-dependently ameliorated skin cancer incidence and the multiplicity in the animal models by reducing the release of inflammation-related cytokines, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-18 (IL-18), interleukin-6 (IL-6), cyclooxygenase 2 (COX2) and transforming growth factor β-1 (TGF-β1). Suppression of the nuclear factor (NF)-κB signaling pathway by SR was effective to prevent skin carcinogenesis. Furthermore, TUNEL analysis indicated that compared to the DMBA/TPA group, enhanced apoptosis was observed in the DMBA/TPA+SR group. In addition, p53 expression levels were increased by SR in the DMBA/TPA-induced mice. Therefore, SR was effective for inducing apoptosis during skin cancer progression triggered by DMBA/TPA. Consistently, p21, p53 upregulated modulator of apoptosis (PUMA), Bax and caspase-3 were highly induced by SR to enhance the apoptotic response for preventing skin cancer. Moreover, in vitro, we found that SR dramatically reduced the inflammatory response, while enhancing the aoptotic response by blocking NF-κB and activating caspase-3 pathways, respectively. In addition, flow cytometric analysis further confirmed the induction of apoptosis by SR in DMBA-treated cells in vitro. Taken together, the in vivo and in vitro studies illustrated that SR might be a promising compound to reduce skin cancer risk.

Feng Y, Shi J, Jiao Z, et al.
Mechanism of bisphenol AF-induced progesterone inhibition in human chorionic gonadotrophin-stimulated mouse Leydig tumor cell line (mLTC-1) cells.
Environ Toxicol. 2018; 33(6):670-678 [PubMed] Related Publications
Bisphenol AF (BPAF) has been shown to inhibit testicular steroidogenesis in male rats. However, the precise mechanisms related to the toxic effects of BPAF on reproduction remain poorly understood. In the present study, a mouse Leydig tumor cell line (mLTC-1) was used as a model to investigate the mechanism of steroidogenic inhibition and to identify the molecular target of BPAF. Levels of progesterone and the concentration of cyclic adenosine monophosphate (cAMP) in cells exposed to BPAF were detected, and expression of key genes and proteins in steroid biosynthesis was assessed. The results showed that BPAF exposure decreased human chorionic gonadotrophin (hCG)-stimulated progesterone production in a dose-dependent manner. The 24-h IC

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