Gene Summary

Gene:GOPC; golgi associated PDZ and coiled-coil motif containing
Aliases: CAL, FIG, PIST, GOPC1, dJ94G16.2
Summary:This gene encodes a Golgi protein with a PDZ domain. The PDZ domain is globular and proteins which contain them bind other proteins through short motifs near the C-termini. Mice which are deficient in the orthologous protein have globozoospermia and are infertile. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:Golgi-associated PDZ and coiled-coil motif-containing protein
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: GOPC (cancer-related)

Riyahi N, Safaroghli-Azar A, Sheikh-Zeineddini N, et al.
Synergistic Effects of PI3K and c-Myc Co-targeting in Acute Leukemia: Shedding New Light on Resistance to Selective PI3K-δ Inhibitor CAL-101.
Cancer Invest. 2019; 37(7):311-324 [PubMed] Related Publications
Enthusiasms into the application of PI3K-δ inhibitor CAL-101 has been muted due to the over-activation of compensatory molecules. Our results delineated that c-Myc suppression using 10058-F4 enhanced CAL-101 cytotoxicity in less sensitive cells through different mechanisms based on p53 status; while CAL-101-plus-10058-F4 induced G1 arrest in wild-type p53-expressing leukemic cells, no conspicuous increase in G1 was noted in U937 cells harboring mutant p53. Conclusively, this study shed lights on the role of c-Myc oncoprotein in acute leukemia cells sensitivity to PI3K inhibitor and outlined that the combination of c-Myc inhibitor and CAL-101 may be a promising therapeutic approach in leukemia.

Zarei S, Reza JZ, Jaliani HZ, et al.
Effects of carfilzomib alone and in combination with cisplatin on the cell death in cisplatin-sensitive and cisplatin-resistant ovarian carcinoma cell lines.
Bratisl Lek Listy. 2019; 120(6):468-475 [PubMed] Related Publications
BACKGROUND: Previous studies on the efficacy of platinum-based drugs and selective inhibitors of proteasome have revealed promising outcomes. This study is aimed to evaluate the effects of the combination of cisplatin and carfilzomib on the cell death induction and drug efflux transporters expression in cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) ovarian cancer cells lines.
METHODS: MTT cytotoxic assay was conducted to determine the cytotoxicity. Drug interactions were analyzed based on Chou-Talalay's principles and real-time PCR analysis was performed to determine possible alterations in mRNA levels of MRP1 and BCRP.
RESULTS: A2780s cells were more susceptible to both cisplatin and carfilzomib while analyses of drug interactions between the two agents showed synergistic effects in all affected fractions of drug-treated A2780s and A2780cp cells (CI<0.9) with the combination indices being significantly lower in A2780cp cells (p < 0.01). We also found that although mRNA levels of BCRP and MRP1 were significantly altered in both cells exposed to each drug alone, only the combination regimen was able to significantly reduce the mRNA levels of these genes in A2780cp cells (p<0.001).
CONCLUSION: This combination might be a potential strategy for suppressing cell growth via downregulating the drug efflux transporters expression, especially in cisplatin-resistant ovarian cancer cells (Fig. 3, Ref. 45).

Cebecioglu R, Yildirim M, Akagunduz D, et al.
Synergistic effects of quercetin and selenium on oxidative stress in endometrial adenocarcinoma cells.
Bratisl Lek Listy. 2019; 120(6):449-455 [PubMed] Related Publications
OBJECTIVE: The effects of quercetin and selenium on oxidative stress in endometrial adenocarcinoma cells are unclear. In this study, the effects of quercetin and selenium on oxidative stress caused by both hydrogen peroxide and UV radiation in endometrial adenocarcinoma cells were examined.
METHODS: The viability of endometrial adenocarcinoma cells cultured in vitro and treated with different concentrations of quercetin and sodium selenite was measured using the MTT assay. Malondialdehyde (MDA) levels were investigated, and expression levels of BAD and p53 genes were analysed using real‑time quantitative polymerase chain reaction. Acridine orange/ethidium bromide staining technique was applied to detect apoptosis. Mass attenuation coefficient of each quercetin and sodium selenite combinations was evaluated using Monte Carlo simulation.
RESULTS: The combination of quercetin and sodium selenite enhanced cell viability, and reduced MDA levels. The expression levels of BAD and p53 genes decreased by combined treatment with quercetin and selenium while showing synergistic effects in terms of gene expression. Fluorescent microscopic examination showed a decrease in apoptotic cells in endometrial adenocarcinoma cells treated with the combination of quercetin and selenium.
CONCLUSIONS: For the first time, selenium and quercetin have synergistic cytoprotective and radioprotective effects on oxidative stress caused by hydrogen peroxide in endometrial adenocarcinoma cells for the first time (Tab. 1, Fig. 7, Ref. 39).

Mohamedi Y, Fontanil T, Cobo T, et al.
Antitumor Potential of Fibulin-5 in Breast Cancer Cells Depends on Its RGD Cell Adhesion Motif.
Cell Physiol Biochem. 2019; 53(1):87-100 [PubMed] Related Publications
BACKGROUND/AIMS: Different components of the tumor microenvironment can be either tumor-promoting or tumor-suppressive agents depending on factors which are not fully understood. Fibulins are components of the extracellular matrix from different tissues and constitute a clear example of this dual function. In fact, fibulins may either support tumor growth or abolish progression of malignant cells depending on the crosstalk between tumor cells and their surrounding stroma through mechanisms that remain to be elucidated. Among all fibulins, fibulin-5 contains a particular structural hallmark which consists in the presence of a RGD motif within its architecture. Previous reports have highlighted the importance of the interaction of this motif with integrins, and not only in normal functions but also in a tumor context.
METHODS: Site-Directed Mutagenesis technique was employed to introduce the change RGD to RGE (RGD-to-RGE) within Fbln5 cDNA sequence. Cell proliferation was measured using the MTT assay or by counting Ki-67 positive cell nuclei. Cell adhesion was analysed using culture plates coated with different extracellular matrix components. Cell invasion was evaluated using 24-well Matrigel-coated invasion chambers, and mammosphere formation was monitored using ultralow attachment culture plates. BALB/c mice were employed to induce subcutaneous tumors.
RESULTS: The RGD-to-RGE change alters the capacity of breast cancer cells to adhere to different extracellular matrix proteins as well as to α
CONCLUSION: These data highlight the importance of the RGD motif of fibulin-5 to induce antitumor effects and provide new insights into the involvement of fibulins in tumor processes.

Li JY, Huang WX, Zhou X, et al.
Numb inhibits epithelial-mesenchymal transition via RBP-Jκ-dependent Notch1/PTEN/FAK signaling pathway in tongue cancer.
BMC Cancer. 2019; 19(1):391 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Oral cancer has been estimated as the sixth most frequent solid cancer all over the world, in which tongue squamous cell carcinoma (TSCC) is the most common type of oral cancers. However, the mechanism of TSCC metastasizing to lymph node and distant sites has not been completely understood.
METHODS: In this study, RT-qPCR method was used to detect the mRNA level of Numb, PTEN and Notch1 genes, as well as EMT-associated genes. Western blot assay was utilized to detect protein level of these genes. In addition, we determined cell proliferation by MTT assay and employed transwell invasion assay and wound healing assay to probe the abilities of invasion and migration, respectively. To investigate the role of PTEN, its inhibitor VO-Ohpic trihydrate was used to treat SCC-4 and CAL27 cells.
RESULTS: We found that Numb expression was downregulated in SCC-9 and CAL-27 cells compared to NHOK cells. Instead, Notch1 level in SCC-9 and CAL-27 cells were higher than that in NHOK cells. Furthermore, the results showed that Numb overexpression significantly suppressed proliferation, migration and invasion of SCC-9 and CAL-27 cells via regulating Notch1 signaling and EMT-related genes expression. By contrast, we observed that RBP-Jκ knockdown had an inhibitory role in proliferation, migration and invasion of SCC-9 and CAL-27 cells. In cells with Numb overexpression or RBP-Jκ knockdown, p-FAK and EMT-related genes were remarkably regulated.
CONCLUSIONS: Our findings provide new mechanism of understanding the metastasis of TSCC and help develop therapeutic strategies for treating tongue cancer.

Zheng KB, Xie J, Li YT, et al.
Knockdown of CERB expression inhibits proliferation and migration of glioma cells line U251.
Bratisl Lek Listy. 2019; 120(4):309-315 [PubMed] Related Publications
BACKGROUND: Glioma is a type of tumor that occurs in the brain and accounts for almost 30 % of all brain and central nervous system tumors and 80 % of all malignant brain tumors. In this study, we investigate the role of cAMP response element-binding protein (CREB) in the progression of glioma.
METHODS: Tissue samples from glioma patients were collected and examined for expression of CREB and its correlation with tumor grades. CREB was then knocked down via siRNA to see if reduced expression of CREB affects cell proliferation and migration. Factors involved in cell cycles, adhesion and apoptosis were examined as well. Moreover, CRESP/CAS9 mediated knockout of CREB was conducted and athymic Nude mice model was used to investigate CREB's role in vivo.
RESULTS: The evaluated expression level of CREB in glioma patients was correlated with tumor grades. Knockdown of CREB via siRNA in glioma cell line U251 significantly inhibited the proliferation and migration of tumor cells. Moreover, CyclinD1 and Bcl-2 expression were reduced, as well as phosphorylation of IRK1/2 and AKT. Additionally, knockout of CREB via CRESP/CAS9 inhibited tumor formation of U251 cells in athymic Nude mice model.
CONCLUSIONS: In conclusion, our data suggest that over expression of CREB may contribute to progression of glioma and knockdown of CREB expression may serve as a novel target for therapy (Tab. 1, Fig. 6, Ref. 25).

Korourian A, Madjd Z, Roudi R, et al.
Induction of miR-31 causes increased sensitivity to 5-FU and decreased migration and cell invasion in gastric adenocarcinoma.
Bratisl Lek Listy. 2019; 120(1):35-39 [PubMed] Related Publications
Drug resistance is the main obstacle in the treatment of gastric cancer, the third most common cause of cancer-related death in the world. Due to their small size, easy entrance to cells and multiple targets, microRNAs (miRs) are considered novel and attractive targets. In the current study, parental MKN-45, MKN-45-control vector, and MKN-45-miR-31 populations were compared in terms of cell cycle transitions, migration, cell invasion, and proliferation. In addition, downstream targets of miR-31, including E2F6, and SMUG1 were examined using Real-time RT-PCR and western blotting. MKN-45-miR-31 showed an increased sensitivity to 5-FU, decreased migration and cell invasion compared to the control groups (p = 0.0001, p = 0.01 and p = 0.01, respectively). There was a significant increase in the percentage of cells in G1/pre-G1 phase in MKN-45-miR-31 relative to the control groups (p = 0.001). Induction of miR-31 expression in MKN-45 caused a significant reduction of E2F6 and SMUG1 genes. Our findings indicated that induction of miR-31 expression could increase drug sensitivity, and diminish tumor cell migration and invasion of gastric cancer cells. Therefore, miR-31 can be considered as a potential target molecule in the targeted therapy of gastric cancer (Fig. 2, Ref. 43). Keywords: gastric cancer, miR-31, drug resistance, E2F6, SMUG1.

Ghanbarpanah E, Kohanpour MA, Hosseini-Beheshti F, et al.
Structure and function of FUS gene in prostate cancer.
Bratisl Lek Listy. 2018; 119(10):660-663 [PubMed] Related Publications
BACKGROUND: FUS reduces the proliferator factors such as cyclin D1 and Cdk6, and increases Cdk and p27. Therefore, FUS prevents the growth of prostate cancer cells.
METHODS: This review tried to summarize data about FUS gene expression in correlation with the degree of prostate cancer. To find the relevant studies, the search in PubMed, Science Direct, and Scopus were performed.
RESULTS: Increasing the expression of FUS decreases and increases the rate of apoptosis of prostate cancer cells, respectively. In fact, FUS reduces the proliferator factors such as: cyclin D1 and Cdk6, and increases Cdk (an anti-proliferation factor) and p27 (a proliferative inhibitory factor). Therefore, FUS prevents the growth of prostate cancer cells. An immuno-histochemical analysis showed that FUS gene expression had an inverse correlation with the degree of prostate cancer, which suggests that patients with higher levels of FUS are more likely to survive and less likely to have bone pain.
CONCLUSION: The key to FUS is the signaling of the androgen receptor and the progression of the cell cycle in prostate cancer. Based on these findings, we might be able to consider exogenous expression of FUS as a treatment for prostate cancer (Fig. 1, Ref. 32).

Ibrahimi M, Jamalzei B, Akbari ME, et al.
Association between interleukin 4 (IL-4) VNTR, gene polymorphism, and breast cancer susceptibility in Iranian population: experimental and web base analysis.
Bratisl Lek Listy. 2018; 119(10):651-654 [PubMed] Related Publications
BACKGROUND: Breast cancer (BC) is one of the most common types of cancer and the second leading cause of cancer death among women. Epidemiological studies showed that BC is linked to genetic and environmental factors, and inheritance plays a key role in the pathobiology of this disease. Interleukin 4 (IL-4) is a key differentiation cytokine and is produced by Th2 and activates Th2 development. Hence the current study aimed to assess the possible association between interleukin 4 (IL-4) VNTR polymorphism, and BC susceptibility in a sample of Iranian population.
MATERIAL AND METHODS: IL-4 VNTR polymorphism was evaluated in 150 women with BC and 150 age-matched healthy women by polymerase chain reaction method.
RESULT: Among 3 possible alleles for IL-4 gene, we only observed 2 alleles. Current findings indicate that RP2/RP2 genotypes can be regarded as potent protective factors against breast cancer (OR = 0.929 [95%CI, 0.929-0.995]).
CONCLUSION: Our result showed that the RP2/RP2 genotype of the IL-4 VNTR polymorphism could be a protective factor for BC susceptibility (Tab. 2, Fig. 1, Ref. 46).

Li N, Nan CC, Zhong XY, et al.
miR-182-5p Promotes Growth in Oral Squamous Cell Carcinoma by Inhibiting CAMK2N1.
Cell Physiol Biochem. 2018; 49(4):1329-1341 [PubMed] Related Publications
BACKGROUND/AIMS: Emerging evidence suggests that the propagation of oral squamous cell carcinoma (OSCC) is influenced by the abnormal expression of microRNAs (miRNAs). This study aimed to characterize the involvement of miR-182-5p in OSCC by targeting the calcium/ calmodulin-dependent protein kinase II inhibitor CAMK2N1.
METHODS: miR-182-5p expression was quantified in OSCC tissues and cell lines with reverse transcription polymerase chain reaction (RT-PCR). Cell colony formation, Cell Counting Kit-8 (CCK-8), Ki-67, and nude mouse xenograft assays were used to characterize the role of miR-182-5p in the proliferation of OSCC. A miR-182-5p target gene was identified with western blotting, RT-PCR, and luciferase activity assays. OSCC patient survival based on CAMK2N1 expression was also analyzed.
RESULTS: miR-182-5p was up-regulated in in vitro cell lines and in vivo clinical OSCC samples. CCK-8, colony formation, and Ki-67 assays revealed that miR-182-5p promoted the growth and proliferation of OSCC cells. miR-182-5p directly targeted CAMK2N1, as evidenced by luciferase assays and target prediction algorithms. CAMK2N1 operated as a tumor suppressor gene in patients with OSCC. Down-regulating miR-182-5p expression in the CAL-27 cell line restored CAMK2N1-mediated OSCC cell proliferation. miR-182-5p expression inhibited the activation of AKT, ERK1/2, and NF-κB. Mice injected with CAL-27 cells transfected with miR-182-5p-inhibitor demonstrated a significant increase in tumor size and weight and increased CAMK2N1 mRNA and protein expression compared with the miR-negative control group.
CONCLUSION: The miR-182-5p-CAMK2N1 pathway can be potentially targeted to regulate the proliferation of OSCC cells.

Tomcikova D, Gerinec A, Busanyova B, et al.
Incomprehensible treatment of retinoblastoma with high doses of vitamin C.
Bratisl Lek Listy. 2018; 119(8):513-515 [PubMed] Related Publications
PURPOSES: To inform about a case of neglected retinoblastoma that was left untreated for more than 3 years by parents. During this time period the local finding worsened from endophytic retinoblastoma group B according IIRC (ABC classification) to extraorbital propagation.
BACKGROUND: Retinoblastoma is the most common intraocular tumor in childhood, that occurs approximately in 1 : 15-20 000 births worldwide. In European region cases of extraocular propagation are very infrequent. Extraorbital propagation is extremely rare in middle and high income countries.
METHODS: We report the preoperative ophthalmological findings, MRI imaging, treatment methods and postoperative results of this case.
RESULTS: After initial dose of six courses of chemotherapy patient underwent surgery (orbital exenteration). In postoperative period patient received two more courses of chemotherapy. In spite of progressed stage of the disease, we obtained good results with our therapy.
CONCLUSIONS: We suppose that good treatment results, in spite of extraordinary long lag interval and hopeless pretreatment condition, caused by alternative therapy with high doses vitamin C and no protein intake, were caused by therapeutic naïve retinoblastoma with an absence of RB1 gene mutation (Fig. 6, Ref. 7).

Akin DF, Oner DA, Kurekci E, Akar N
Determination of CEBPA mutations by next generation sequencing in pediatric acute leukemia.
Bratisl Lek Listy. 2018; 119(6):366-372 [PubMed] Related Publications
OBJECTIVES: The CCAAT/enhancer-binding protein-alpha (CEBPA) is lineage-specific transcription factor in the hematopoietic system. In this study, we aimed on the clinical features and the prognostic significance associated with CEBPA mutations in 30 pediatric patients with acute leukemia.
METHODS: In addition, the association between found variants and mutations of Ten-Eleven-Translocation 2 (TET2), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Casitas B-cell lymphoma (CBL), FLT3 (Fms-Related Tyrosine Kinase), JAK2 (Januse Kinase-2) and Nucleophosmin 1 (NPM1) were analyzed, which are important prognostic risk factors for pediatric acute leukemia patients. The entire CEBPA coding region was screened using the NGS method.
RESULTS: CEBPA mutations were detected in 16 (53.3 %) of 30 patients. In total, ten distinct of nucleotide changes were identified in 30 patients, including 6 novel and 4 known mutations by sequencing the entire CEBPA gene. We found 6 frame shift mutations, 1 missense mutation, 3 synonymous variants. The most common mutation was the c.487del G resulting p.Glu163Ser in 5 cases. Three patients carried CEBPA double mutations.
CONCLUSION: The detected variants in this article seemed to be the first screening results of genes studied by NGS in pediatric acute leukemia patients. Our results also showed some degree of association between FLT3-ITD, TET2, KRAS, CBL and CEBPA mutations (Tab. 4, Fig. 1, Ref. 24).

Wang Y, Lin X, Fu X, et al.
Long non-coding RNA BANCR regulates cancer stem cell markers in papillary thyroid cancer via the RAF/MEK/ERK signaling pathway.
Oncol Rep. 2018; 40(2):859-866 [PubMed] Related Publications
Thyroid cancer is one of the most common malignant tumors of the endocrine system. Among all thyroid cancers, papillary thyroid carcinoma (PTC) is the most common type. The BRAF-activated non-coding RNA (BANCR) is a 693-bp nucleotide transcript which was first identified in melanoma. However, the role of BANCR in the development of thyroid cancer remains unclear. Therefore, the present study investigated the potential involvement of BANCR in the development of thyroid cancer in vitro using patient tissue samples and a panel of thyroid cancer cell lines, and in vivo using a xenograft mouse model. We observed that BANCR was expressed at a higher level in human thyroid tumor tissues than that noted in the adjacent normal tissues. The expression level of BANCR differed between cultured thyroid cancer cell lines; BANCR expression was lower in the BCPAP cell line than that observed in the CAL-62, WRO and FTC-133 cell lines. Western blot analysis and flow cytometry revealed that overexpression of BANCR in the BCPAP cell line resulted in increased expression of the cancer stem cell markers, LGR5 and EpCAM. Single-clone formation experiments showed that upregulated expression of BANCR in the BCPAP cell line promoted an increase in the number of clones formed. Similarly, in microsphere formation experiments, overexpression of BANCR resulted in increased number and size of microspheres compared with the control cell line. Western blotting experiments showed that BANCR overexpression in BCPAP upregulated the expression of phosphorylated c-Raf, MEK1/2 and ERK1/2. Inhibition of c-Raf via U0126 decreased the expression of LGR5 and EpCAM, as well as phosphorylated levels of c-Raf, MEK1/2 and ERK1/2 in the BCPAP cells, compared to levels in the DMSO controls. In the xenograft mouse model, BANCR overexpression in the thyroid cancer cells significantly increased tumor growth. Taken together, these results suggest that BANCR plays a role in PTC development by regulating the expression of cancer stem cell markers LGR5 and EpCAM via the c-Raf/MEK/ERK signaling pathway. Therefore, BANCR may be used as a novel prognostic marker for PTC.

Pan L, Yang H, Xu C, et al.
ZNF750 inhibited the malignant progression of oral squamous cell carcinoma by regulating tumor vascular microenvironment.
Biomed Pharmacother. 2018; 105:566-572 [PubMed] Related Publications
OBJECTIVE: Squamous cell carcinoma is often associated with the deletion or mutation of zinc finger protein 750 (ZNF750), its deletion or mutation is associated with squamous epithelial malignant biological characteristics. The present study is to explore the mechanism of ZNF750 to suppress the tumor malignant process by regulation tumor microenvironment.
METHODS: To evaluate the changes of tumor microenvironment in oral squamous cells carcinoma cell line CAL-27 cell, the expression of angiogenin, vascular endothelial growth factor (VEGF), prolyl hydroxylase 2 (PHD2), G protein signal regulated protein 5 (RGS5), integrin A5 (ITGA5), integrin B1 (ITGB1) and CD44 were detected by Western-blot. The changes of platelet derived growth factor (PDGFB) and tumor vascular marker CD105 (Endoglin) mRNA were estimated by qPCR. The effect of over-expressed ZNF750 on cell viability and lateral migration capacity was investigated by CCK-8 and cell scratch assay in three oral squamous cells carcinoma.
RESULTS: ZNF750 could effectively inhibit the protein or mRNA expression of angiogenin, VEGF, RGS5 and CD105, repressed the cell adhesion molecules ITGA5, ITGB1 and CD44, but up-regulate the protein or mRNA expression of PHD2 and PDGFB. The cell viability and lateral migration ability of three oral squamous cells carcinoma were reduced by over-expression of ZNF750.
CONCLUSION: ZNF750 could modulate the tumor vascular microenvironment to inhibit the oral squamous cells carcinoma malignant progression.

Sakamoto K, Katayama R, Asaka R, et al.
Recurrent 8q24 rearrangement in blastic plasmacytoid dendritic cell neoplasm: association with immunoblastoid cytomorphology, MYC expression, and drug response.
Leukemia. 2018; 32(12):2590-2603 [PubMed] Related Publications
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare skin-tropic hematological malignancy of uncertain pathogenesis and poor prognosis. We examined 118 BPDCN cases for cytomorphology, MYC locus rearrangement, and MYC expression. Sixty-two (53%) and 41 (35%) cases showed the classic and immunoblastoid cytomorphology, respectively. Forty-one (38%) MYC

Juan C, Hua Q, Ruping Z, Tingting W
miRNA-489 as a biomarker in diagnosis and treatment of cervical cancer.
Bratisl Lek Listy. 2018; 119(5):278-283 [PubMed] Related Publications
miRNA-489 was shown to be a suppressor factor in many cancers, however, evidence on the effects and mechanism of miRNA-489 in progression of cervical cancer is limited. So we aimed to determine the function of miRNA-489 in cervical cancer proliferation and apoptosis in our present study. Interestingly, we found that miRNA-489 was significantly down-regulated in cervical cancer tissues. miRNA-489 overexpression inhibited the cell proliferation and improved the cell apoptosis of cervical cancer cells. Further, miRNA-489 over-expression suppressed the activation of PI3K and AKT, and stimulated P53 proteins expression. In conclusion, our results suggested that miRNA-489 may be considered as a biomarker in cervical cancer and had suppressed the cell proliferation and stimulated cell apoptosis via PI3K/AKT/P53 signaling pathway (Fig. 5, Ref. 26). Text in PDF

Lombardo GE, Maggisano V, Celano M, et al.
Mol Cancer Ther. 2018; 17(6):1187-1195 [PubMed] Related Publications
The high frequency of

Ferri GM, Guastadisegno CM, Intranuovo G, et al.
Maternal Exposure to Pesticides, Paternal Occupation in the Army/Police Force, and CYP2D6*4 Polymorphism in the Etiology of Childhood Acute Leukemia.
J Pediatr Hematol Oncol. 2018; 40(4):e207-e214 [PubMed] Related Publications
Epidemiologic studies have suggested that parental occupations, pesticide use, environmental factors, and genetic polymorphism are involved in the etiology of childhood acute leukemia (CAL). In total, 116 cases of CAL and 162 controls were recruited and submitted to blood drawing to assess the presence of genetic polymorphisms. Parental occupations, pesticides exposure, and other potential determinants were investigated. Increased risk for CAL was associated with prenatal maternal use of insecticides/rodenticides (odds ratio [OR]=1.87; 95% confidence intervals [CI], 1.04-3.33), with subjects living <100 m from pesticide-treated fields (OR=3.21; 95% CI, 1.37-7.53) and with a paternal occupation as traffic warden/policeman (OR=4.02; 95% CI, 1.63-9.87). Associations were found between CAL and genetic polymorphism of CYP2D6*4 for homozygous alleles (mutant type/mutant type: OR=6.39; 95% CI, 1.17-34.66). In conclusion, despite the small sample size, maternal prenatal exposure to pesticides, paternal occupation as a traffic warden/police officer, and CYP2D6*4 polymorphism could play a role in the etiology of CAL.

Feng QQ, Dong ZQ, Zhou Y, et al.
miR-16-1-3p targets TWIST1 to inhibit cell proliferation and invasion in NSCLC.
Bratisl Lek Listy. 2018; 119(1):60-65 [PubMed] Related Publications
In our study, the impact of miR-16-1-3p on cell proliferation and invasion in NSCLC was explored. miR-16-1-3p mimics were transfected to A549 cells for miR-16-1-3p overexpression. qRT- PCR and Western blot were applied to explore the relative expression of mRNA and protein in A549 cells. Furthermore, the cell proliferation capability was determined by MTT assay. Additionally, cell migration and invasion were measured using a scratch assay and transwell assay, respectively. Moreover, TargetScan and luciferase reporter assay was utilized to investigate the target of miR-16-1-3p. The results indicated that miR-16-1-3p was downregulated in NSCLC cells and upregulation of miR-16-1-3p was able to inhibit the expression of TWIST1. In addition, the reduced cell proliferation, inhibited cell migration and invasion were observed in miR-16-1-3p mimic group compared to the negative control group. The luciferase reporter gene showed that TWIST1 was a target of miR-16-1-3p. Therefore, the present study demonstrated that miR-16-1-3p may suppress A549 cell proliferation, migration and invasion by targeting TWIST1. Thus, miR-16-1-3p might play important roles in NSCLC development, which provides a novel aspect for NSCLC investigation (Fig. 6, Ref. 26).

Shu Y, Ye W, Gu YL, Sun P
Blockade of miR-663b inhibits cell proliferation and induces apoptosis in osteosarcoma via regulating TP73 expression.
Bratisl Lek Listy. 2018; 119(1):41-46 [PubMed] Related Publications
OBJECTIVE: This study aimed to investigate the exact role of miR-663b in osteosarcoma (OS) progression and further explore the underlying molecular mechanisms.
MATERIALS AND METHODS: The miR-663b expression in human OS cell lines was determined by qRT-PCR, and the results suggested that miR-663b was highly expressed in human OS cells. TargetScan was used to predict the potential targets of miR-663b, and the prediction was confirmed by dual-luciferase reporter assay. To investigate the role of miR-663b in OS, miR-663b was down-regulated in U2OS cells using miR-663b inhibitor. CCK8 and flow cytometry were preformed to investigate the proliferation and apoptosis of U2OS cells. Moreover, qRT-PCR and western blot analysis were performed to measure the mRNA and protein expression.
RESULTS: We found that miR-663b directly targets TP73 and negatively regulates TP73 expression. MiR-663b inhibitor significantly decreased the proliferation ability of U2OS cells, while the percentage of apoptotic cells was markedly increased. The level of Bcl-2 was notably inhibited by miR-663b inhibitor, while Bax expression was significantly enhanced. Moreover, miR-663b down-regulation promoted p53 and p21 expression in U2OS cells.
CONCLUSIONS: MiR-663b down-regulation represses proliferation and induces apoptosis in OS by targeting TP73. Therefore, we provide a potential therapeutic target for OS treatment (Fig. 6, Ref. 27).

Wang ZY, Hu M, Dai MH, et al.
Upregulation of the long non-coding RNA AFAP1-AS1 affects the proliferation, invasion and survival of tongue squamous cell carcinoma via the Wnt/β-catenin signaling pathway.
Mol Cancer. 2018; 17(1):3 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Long non-coding RNA (lncRNA) actin filament associated protein 1 antisense RNA1 (AFAP1-AS1) is oriented in an antisense direction to the protein-coding gene AFAP1 in the opposite strand. Previous studies showed that lncRNA AFAP1-AS1 was upregulated and acted as an oncogene in a variety of tumors. However, the expression and biological functions of lncRNA AFAP1-AS1 in tongue squamous cell carcinoma (TSCC) are still unknown.
METHODS: The expression level of AFAP1-AS1 was measured in 103 pairs of human TSCC tissues and corresponding adjacent normal tongue mucous tissues. The correlation between AFAP1-AS1 and the clinicopathological features was evaluated using the chi-square test. The effects of AFAP1-AS1 on TSCC cells were determined via a CCK-8 assay, clone formation assay, flow cytometry, wound healing assay and transwell assay. Furthermore, the effect of AFAP1-AS1 knockdown on the activation of the Wnt/β-catenin signaling pathway was investigated. Finally, CAL-27 cells with AFAP1-AS1 knockdown were subcutaneously injected into nude mice to evaluate the effect of AFAP1-AS1 on tumor growth in vivo.
RESULTS: In this study, we found that lncRNA AFAP1-AS1 was increased in TSCC tissues and that patients with high AFAP1-AS1 expression had a shorter overall survival. Short hairpin RNA (shRNA)-mediated AFAP1-AS1 knockdown significantly decreased the proliferation of TSCC cells. Furthermore, AFAP1-AS1 silencing partly inhibited cell migration and invasion. Inhibition of AFAP1-AS1 decreased the activity of the Wnt/β-catenin pathway and suppressed the expression of EMT-related genes (SLUG, SNAIL1, VIM, CADN, ZEB1, ZEB2, SMAD2 and TWIST1) in TSCC cells. In addition, CAL-27 cells with AFAP1-AS1 knockdown were injected into nude mice to investigate the effect of AFAP1-AS1 on tumorigenesis in vivo. Downregulation of AFAP1-AS1 suppressed tumor growth and inhibited the expression of EMT-related genes (SLUG, SNIAL1, VIM, ZEB1, NANOG, SMAD2, NESTIN and SOX2) in vivo.
CONCLUSIONS: Taken together, our findings present a road map for targeting the newly identified lncRNA AFAP1-AS1 to suppress TSCC progression, and these results elucidate a novel potential therapeutic strategy for TSCC.

Li Z, Liu J, Li L, et al.
Epithelial mesenchymal transition induced by the CXCL9/CXCR3 axis through AKT activation promotes invasion and metastasis in tongue squamous cell carcinoma.
Oncol Rep. 2018; 39(3):1356-1368 [PubMed] Related Publications
The present study aimed to assess the induction of epithelial-mesenchymal transition (EMT), invasion, and metastasis by the chemokine CXCL9/receptor CXCR3 axis in tongue squamous cell carcinoma (TSCC), unveiling the underlying mechanisms and providing new insights into the prevention and treatment of oral cancer metastasis. The expression levels of CXCL9 and CXCR3 in TSCC tissue specimens were determined by immunohistochemistry, assessing differences between samples with cervical lymph node metastasis and those without. Moreover, protein expression or activity in the TSCC Cal-27 cell line was controlled by neutralizing antibodies, gene transfection, or knock-out. Then, alterations of cell proliferation, migration, invasion, and the cytoskeleton were analyzed by CCK-8, cell scratch, Transwell, and cyto-skeleton staining assays, respectively. Alterations of EMT markers (E-cadherin and vimentin) in Cal-27 cells were detected by immunofluorescence and western blotting. In addition, western blotting was utilized to detect protein expression levels of Akt2, p-Akt2, eIF4E and p-eIF4E, and to explore the regulatory roles and mechanisms of the CXCL9/CXCR3 axis in invasion and metastasis. Significantly increased expression levels of CXCL9 and CXCR3 were detected in tissue specimens with lymph node metastasis compared with those without (P<0.01). Overexpression of CXCL9/CXCR3 in Cal-27 cells resulted in cytoskeleton alterations, decreased E-cadherin expression, increased vimentin levels, enhanced migration and invasion (P<0.05), and increased phosphorylated Akt2 and eIF4E levels (P<0.05). These results revealed that in TSCC, the CXCL9/CXCR3 axis could activate the Akt signaling pathway, with EMT and cytoskeleton rearrangement, promoting invasion and metastasis.

Renault V, Tost J, Pichon F, et al.
aCNViewer: Comprehensive genome-wide visualization of absolute copy number and copy neutral variations.
PLoS One. 2017; 12(12):e0189334 [PubMed] Free Access to Full Article Related Publications
MOTIVATION: Copy number variations (CNV) include net gains or losses of part or whole chromosomal regions. They differ from copy neutral loss of heterozygosity (cn-LOH) events which do not induce any net change in the copy number and are often associated with uniparental disomy. These phenomena have long been reported to be associated with diseases and particularly in cancer. Losses/gains of genomic regions are often correlated with lower/higher gene expression. On the other hand, loss of heterozygosity (LOH) and cn-LOH are common events in cancer and may be associated with the loss of a functional tumor suppressor gene. Therefore, identifying recurrent CNV and cn-LOH events can be important as they may highlight common biological components and give insights into the development or mechanisms of a disease. However, no currently available tools allow a comprehensive whole-genome visualization of recurrent CNVs and cn-LOH in groups of samples providing absolute quantification of the aberrations leading to the loss of potentially important information.
RESULTS: To overcome these limitations, we developed aCNViewer (Absolute CNV Viewer), a visualization tool for absolute CNVs and cn-LOH across a group of samples. aCNViewer proposes three graphical representations: dendrograms, bi-dimensional heatmaps showing chromosomal regions sharing similar abnormality patterns, and quantitative stacked histograms facilitating the identification of recurrent absolute CNVs and cn-LOH. We illustrated aCNViewer using publically available hepatocellular carcinomas (HCCs) Affymetrix SNP Array data (Fig 1A). Regions 1q and 8q present a similar percentage of total gains but significantly different copy number gain categories (p-value of 0.0103 with a Fisher exact test), validated by another cohort of HCCs (p-value of 5.6e-7) (Fig 2B).
AVAILABILITY AND IMPLEMENTATION: aCNViewer is implemented in python and R and is available with a GNU GPLv3 license on GitHub and Docker

Gnanasundram SV, Pyndiah S, Daskalogianni C, et al.
PI3Kδ activates E2F1 synthesis in response to mRNA translation stress.
Nat Commun. 2017; 8(1):2103 [PubMed] Free Access to Full Article Related Publications
The c-myc oncogene stimulates ribosomal biogenesis and protein synthesis to promote cellular growth. However, the pathway by which cells sense and restore dysfunctional mRNA translation and how this is linked to cell proliferation and growth is not known. We here show that mRNA translation stress in cis triggered by the gly-ala repeat sequence of Epstein-Barr virus (EBV)-encoded EBNA1, results in PI3Kδ-dependent induction of E2F1 mRNA translation with the consequent activation of c-Myc and cell proliferation. Treatment with a specific PI3Kδ inhibitor Idelalisib (CAL-101) suppresses E2F1 and c-Myc levels and causes cell death in EBNA1-induced B cell lymphomas. Suppression of PI3Kδ prevents E2F1 activation also in non-EBV-infected cells. These data illustrate an mRNA translation stress-response pathway for E2F1 activation that is exploited by EBV to promote cell growth and proliferation, offering new strategies to treat EBV-carrying cancers.

Yang Y, Hu R, Yan J, et al.
Sevoflurane inhibits the malignant potential of head and neck squamous cell carcinoma via activating the hypoxia‑inducible factor-1α signaling pathway in vitro.
Int J Mol Med. 2018; 41(2):995-1002 [PubMed] Related Publications
Sevoflurane, an inhalational anesthetic, is extensively used during oral cancer surgery. However, the effect of sevoflurane on head and neck squamous cell carcinoma (HNSCC) remains unclear. The objective of the present study was to investigate the effects of sevoflurane on the proliferation, apoptosis and invasion in HNSCC cell lines and the underlying molecular mechanism. The Cell Counting Kit-8 assay was used to evaluate cell proliferation. Apoptosis was analyzed by flow cytometry. Cell invasion was evaluated using the Transwell invasion assay. The expression levels of Akt, p-Akt (Ser473), hypoxia‑inducible factor-1α (HIF-1α), Fas and Bcl-2 were measured by western blotting. Significant inhibition of cell proliferation and induction of apoptosis were observed in FaDu and CAL-27 cells following sevoflurane treatment. The expression of Akt, p-Akt (Ser473) and Bcl-2 was supressed, while that of Fas was significantly increased, which was partly associated with the activation of the HIF-1α pathway. In addition, the results revealed a statistically significant inhibition of cell invasion in the FaDu cell line following exposure to 2 and 4% sevoflurane for 2, 4, 6 and 8 h. Therefore, the present study demonstrated that sevoflurane decreased the malignant behavior of HNSCC cell lines in vitro, which was associated with activation of the HIF-1α pathway.

Kuo MC, Lin TH, Sun CF, et al.
The clinical and prognostic relevance of driver mutations in 203 Taiwanese patients with primary myelofibrosis.
J Clin Pathol. 2018; 71(6):514-521 [PubMed] Related Publications
AIMS: We investigated the clinical and prognostic relevance of the mutational status of driver genes with allele burden and endogenous erythroid colony (EEC) growth in 203 Taiwanese patients with primary myelofibrosis (PMF).
METHODS: Pyrosequencing was used to detect
RESULTS: The frequencies of the three driver mutations and triple-negative status were similarly distributed between pre-PMF and overt PMF patients, except that pre-PMF patients had a higher incidence of
CONCLUSIONS: Our study showed that EEC growth, a higher

Zhang SZ, Cai L, Li B
MEG3 long non-coding RNA prevents cell growth and metastasis of osteosarcoma.
Bratisl Lek Listy. 2017; 118(10):632-636 [PubMed] Related Publications
OBJECTIVE: This study aimed to investigate the role of long non-coding RNA MEG3 (lncRNA MEG3) in osteosarcoma (OS) and further explore the underlying molecular mechanism.
MATERIALS AND METHODS: The expression profiles of MEG3 in OS cell lines and normal osteoblast cell line were detected by qRT-PCR. MEG3 was over-expressed in OS cell line by using LV-MEG3. MTT and colony-formation assays were applied for cell proliferation analysis. Cell migration assay was applied to investigate the cell migration ability. In addition, the expression levels of cell growth and metastasis related factors (Notch1, Hes1, TGF-β, N-cadheren and E-cadheren) were determined to illustrate the mechanisms.
RESULTS: We found that compared with normal osteoblast hFOB1.19 cell line, MEG3 was significantly down-regulated in MG63 and U2OS cell lines, particularly in MG-63 cells. MEG3 was significantly up-regulated in MG63 cells by LV-MEG3. Cell proliferation and migration ability were obviously repressed by MEG3 over-expression. In addition, MEG3 over-expression markedly inhibited Notch1, Hes1,TGF-β and N-cadheren expression, and the expression level of E-cadheren was improved.
CONCLUSIONS: These results indicated that MEG3 could prevent cell growth and metastasis of OS by repressing Notch and TGF-β signaling pathway, thus providing a potential therapeutic target for OS treatment (Tab. 1, Fig. 4, Ref. 30).

Baran M, Canoz O, Altuntas H, et al.
Immunohistochemical investigation of P16, P53 and Ki-67's prognostic values in diffuse large B-Cell lymphomas.
Bratisl Lek Listy. 2017; 118(10):602-608 [PubMed] Related Publications
AIM: The aim of this study is to determine the immunohistochemical properties of Ki-67, P53 expression and loss of P16, and to assess their relationship with both clinical parameters and patient survival in DLBCL.
METHOD: Forty patients, diagnosed at the Pathology Department of our institute with nodal DLBCL were selected as the study group. The relationship between P16, P53, Ki-67 expressions and clinical and laboratory parameters like age, gender, performance status, Eastern Cooperative Oncology Group (ECOG), clinical stage, presence of B-symptoms, bone marrow involvement, International Prognostic Index (IPI) score, lactate dehydrogenase (LDH) level, extranodal extension, relapse, C-reactive protein (CRP), sedimentation, number of leukocytes in patients and patient survival were then statistically evaluated.
RESULTS: Our results display no statistically significant correlation between P53 expression and loss of P16, Ki-67 proliferation index and clinical parameters and overall survival (p > 0.05). The only statistically significant relationship was between loss of P16 and stage (p 0.05).
CONCLUSION: According to the results of our study, the loss of P16, P53 gene expression and Ki-67 proliferation index have no effect on life expectancy of patients with DLBCL (Tab. 2, Fig. 2, Ref. 29).

Malik SS, Lythgoe MP, McPhail M, Monahan KJ
Metachronous colorectal cancer following segmental or extended colectomy in Lynch syndrome: a systematic review and meta-analysis.
Fam Cancer. 2018; 17(4):557-564 [PubMed] Free Access to Full Article Related Publications
Around 5% of colorectal cancers are due to mutations within DNA mismatch repair genes, resulting in Lynch syndrome (LS). These mutations have a high penetrance with early onset of colorectal cancer at a mean age of 45 years. The mainstay of surgical management is either a segmental or extensive colectomy. Currently there is no unified agreement as to which management strategy is superior due to limited conclusive empirical evidence available. A systematic review and meta- analysis to evaluate the risk of metachronous colorectal cancer (MCC) and mortality in LS following segmental and extensive colectomy. A systematic review of the PubMed database was conducted. Studies were included/ excluded based on pre-specified criteria. To assess the risk of MCC and mortality attributed to segmental or extensive colectomies, relative risks (RR) were calculated and corresponding 95% confidence intervals (CI). Publication bias was investigated using funnel plots. Data about mortality, as well as patient ascertainment [Amsterdam criteria (AC), germline mutation (GM)] were also extracted. Statistical analysis was conducted using the R program (version 3.2.3). The literature search identified 85 studies. After further analysis ten studies were eligible for inclusion in data synthesis. Pooled data identified 1389 patients followed up for a mean of 100.7 months with a mean age of onset of 45.5 years of age. A total 1119 patients underwent segmental colectomies with an absolute risk of MCC in this group of 22.4% at the end of follow-up. The 270 patients who had extensive colectomies had a MCC absolute risk of 4.7% (0% in those with a panproctocolecomy). Segmental colectomy was significantly associated with an increased relative risk of MCC (RR = 5.12; 95% CI 2.88-9.11; Fig. 1), although no significant association with mortality was identified (RR = 1.65; 95% CI 0.90-3.02). There was no statistically significant difference in the risk of MCC between AC and GM cohorts (p = 0.5, Chi-squared test). In LS, segmental colectomy results in a significant increased risk of developing MCC. Despite the choice of segmental or extensive colectomies having no statistically significant impact on mortality, the choice of initial surgical management can impact a patient's requirement for further surgery. An extensive colectomy can result in decreased need for further surgery; reduced hospital stays and associated costs. The significant difference in the risk of MCC, following segmental or extensive colectomies should be discussed with patients when deciding appropriate management. An individualised approach should be utilised, taking into account the patient's age, co-morbidities and genotype. In order to determine likely germline-specific effects, or a difference in survival, larger and more comprehensive studies are required.

Li D, Liu K, Li Z, et al.
miR-19a and miR-424 target TGFBR3 to promote epithelial-to-mesenchymal transition and migration of tongue squamous cell carcinoma cells.
Cell Adh Migr. 2018; 12(3):236-246 [PubMed] Free Access to Full Article Related Publications
Previous studies indicate that TGFBR3 (transforming growth factor type III receptor, also known as betaglycan), a novel suppressor of progression in certain cancers, is down-regulated in tongue squamous cell carcinoma (TSCC). However, the role of this factor as an upstream regulator in TSCC cells remains to be elucidated. The present study was designed to elucidate whether TGFBR3 gene expression is regulated by two microRNA molecules, miR-19a and miR-424. The study also aimed to determine if these microRNAs promote migration of CAL-27 human oral squamous cells. Immunohistochemistry (IHC) and western blot analyses demonstrated that TGFBR3 protein levels were dramatically down-regulated in clinical TSCC specimens. Conversely, bioinformatics analyses and qRT-PCR results confirmed that both miR-19a and miR-424 were markedly up-regulated in clinical TSCC specimens. In this study, we observed that transfection of a TGFBR3-containing plasmid dramatically inhibited epithelial-to-mesenchymal transition (EMT) and migration in CAL-27 cells. Co-immunoprecipitation analyses also revealed that TGFBR3 forms a complex with the β-arrestin 2 scaffolding protein and IκBα. Furthermore, overexpression of TGFBR3 decreased p-p65 expression and increased IκBα expression; these effects were subsequently abolished following knockdown of β-arrestin 2. Moreover, over-expression of miR-19a and miR-424 promoted migration and EMT in CAL-27 cells. We also observed that the promotion of EMT by miR-19a and miR-424 was mediated by the inhibition of TGFBR3. Our study provides evidence that miR-19a and miR-424 play important roles in the development of TSCC. These results expand our understanding of TGFBR3 gene expression and regulatory mechanisms pertaining to miRNAs.

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