Men of African origin are disproportionately affected by prostate cancer: prostate cancer incidence is highest among men of African origin in the USA, prostate cancer mortality is highest among men of African origin in the Caribbean, and tumour stage and grade at diagnosis are highest among men in sub-Saharan Africa. Socioeconomic, educational, cultural, and genetic factors, as well as variations in care delivery and treatment selection, contribute to this cancer disparity. Emerging data on single-nucleotide-polymorphism patterns, epigenetic changes, and variations in fusion-gene products among men of African origin add to the understanding of genetic differences underlying this disease. On the diagnosis of prostate cancer, when all treatment options are available, men of African origin are more likely to choose radiation therapy or to receive no definitive treatment than white men. Among men of African origin undergoing surgery, increased rates of biochemical recurrence have been identified. Understanding differences in the cancer-survivorship experience and quality-of-life outcomes among men of African origin are critical to appropriately counsel patients and improve cultural sensitivity. Efforts to curtail prostate cancer screening will likely affect men of African origin disproportionately and widen the racial disparity of disease.

Phosphatidylinositol‑3,4,5‑trisphosphate‑dependent Rac exchange factor 2a (PREX2a), which is a regulator of the small guanosine triphosphatase Rac, has recently been reported to have an oncogenic role via the suppression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) activity, and the subsequent activation of phosphoinositide 3‑kinase (PI3K) signaling. However, the detailed role of PREX2a in osteosarcoma (OS) remains unclear. Reverse transcription quantitative polymerase chain reaction and western blotting was used to detect mRNA and protein levels. MTT assay was performed to examine cell proliferation and a Transwell assay and wound healing assay were conducted to examine cell invasion and migration. The present study demonstrated that PREX2a was markedly upregulated in OS cell lines, as compared with in normal osteoblast hFOB1.19 cells. In addition, knockdown of PREX2a expression significantly inhibited OS cell proliferation, whereas overexpression of PREX2a markedly promoted OS cell proliferation. Inhibition of PREX2a also markedly suppressed the invasion and migration of OS cells, at least partly by suppressing the protein expression of matrix metalloproteinase (MMP)2 and MMP9. Conversely, upregulation of PREX2a enhanced OS cell invasion and migration. In addition, PI3K signaling activity was significantly reduced following knockdown of PREX2a, and this was accompanied by an upregulation of PTEN activity. The results of the present study suggested that PREX2a may act as an oncogene in OS via the inhibition of PTEN activity and activation of PI3K signaling.

Galectin-3 is a multifunctional β-galactoside‑binding lectin that is involved in multiple biological functions which are upregulated in malignancies, including cell growth, adhesion, proliferation, progression and metastasis, as well as apoptosis. A previous study has confirmed the roles of galecin-3 overexpression in the biological behavior of Eca109 human esophageal cancer (EC) cells. In the present study, small interfering (si)RNA-mediated galectin-3 silencing was performed to analyze the effects of decreased galectin-3 expression on the biological behavior of EC cells. Western blot and quantitative polymerase chain reaction analyses were utilized to confirm galectin-3 knockdown at the protein and mRNA level (P<0.05 vs. siRNA-control and untransfected groups). Cell proliferation was assessed using the Cell Counting Kit-8 assay. At 72 and 96 h after transfection, the proliferation of Eca109 cells in the siRNA-Gal-3 group was decreased compared with that in the siRNA-Control and untransfected groups (P<0.001 and P=0.004, respectively). Furthermore, Transwell assays demonstrated that inhibition of galecin-3 significantly reduced the migration and invasion of Eca109 cells compared with that in the other groups (P<0.05). Finally, apoptosis of Eca109 cells was detected using Annexin V/7-amino‑actinomycin double-staining and flow cytometric analysis. Galectin-3 knockdown significantly enhanced the apoptotic rate of Eca109 cells compared with that in the siRNA-control and untreated groups (P=0.031 and P=0.047, respectively). In conclusion, following successful knockdown of galecin-3 expression in Eca109 cells, the cell proliferation, migration and invasion were reduced, while the apoptosis was enhanced, which indicates that galectin silencing may represent a therapeutic strategy for EC.

Accumulated evidence have proposed that single nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) are connected to breast cancer (BC) risk. We have done a case-control study with 258 BC patients and 209 control women to examine the potential association of Hsa-mir-603 rs11014002 C>T polymorphisms with BC susceptibility. The polymorphisms were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Our findings showed that the rs11014002 C>T variant was not associated with an increased risk of BC in codominant (OR=0.67, 95%CI=0.42-1.08, P=0.121, CT vs CC; and OR=0.18, 95%CI=0.02-1.67, P=0.170, TT vs CC), dominant (OR=0.64, 95%CI=0.41-1.01, P=0.062, CT+TT vs CC), and recessive (OR=0.20, 95%CI=0.02-1.81, P=0.178, TT vs CC+CT) inheritance models tested. While, the T allele significantly decreased the risk of BC (OR= 0.63; 95% CI =0.41-0.95; P=0.032) compared to C allele. In conclusion, the findings indicated that Mir603 rs11014002 T allele might contribute to decrease the risk of BC in a sample of Iranian population. Further studies with larger sample sizes and different ethnicities are warranted to confirm our findings.

Ribonucleoside-diphosphate reductase subunit M2, also known as ribonucleotide reductase small subunit, is an enzyme that in humans is encoded by the RRM2 gene and also Ribonucleoside-diphosphate reductase large subunit is an enzyme that in humans is encoded by the RRM1 gene. RRM1 is a gene important in determining tumor phenotype, but also induced the expression of PTEN tumor suppressor gene, cell migration, invasion and metastasis formation, and play a preventive role. ERCC2 DNA repair mechanism is associated in more than 20 genes involved in the NER pathway. The aim of this study is to investigate rs13181 ERCC2 (T>G) (Lys751Gln), rs12806698 RRM1 (-269C>A) and rs6759180 (located in the 5'UTR) RRM2 (10126436G>A) gene polymorphisms by using real time PCR technique in patients with NSCLC. 193 NSCLC cases and 141 healthy control cases were included in this study. A significant difference was found between rs12806698 RRM1 genotype distributions (*p: 0.034) and were determined increases the risk of disease approximately 3.044 times AA genotype having (*p: 0.014 OR: 3.044, 95%CI: 1.205-7,688). A significant difference was found between rs6759180 RRM2 genotype distributions (*p: 0.033) and were determined increases the risk of disease approximately 3.49 times GG genotype having (p: 0,009 OR: 3, 49, %95CI:1.291-9,482). It was found significant difference in serum 8-OHdG levels between patients and controls (*p: 0001).

TRAIL mediated signaling in cancer cells has emerged as one amongst the most deeply studied molecular phenomenon. Recent breakthroughs have shown that overexpression of anti-apoptotic proteins, inactivation of pro-apoptotic proteins, transcriptional downregulation of TRAIL, DR4/DR5, degradation of DR/DR5 are some of the mechanisms which dramatically abrogate TRAIL induced apoptosis in cancer cells. Data obtained through genetic studies has highlighted highly polymorphic nature of DR4 and in accordance with this concept, we investigated the association between Head and Neck Cancer and polymorphisms in TRAIL (1595 C/T) and DR4 (C626G and A1322G) gene. We selected 100 patients with Head and Neck Cancer and 100 healthy, sex and age matched volunteers randomly. C626G and A1322G in DR4 gene were analyzed using Polymerase Change Reaction (PCR) - Restriction Fragment Length Polymorphism (RFLP) and Amplification Refractory Mutation System (ARMS) techniques respectively. For TRAIL gene 1595 C>T genotypes, there was no statistically significant role of homozygous CC or TT in Head and Neck cancer. CC was 58% in patients and 49% in controls. CT was 30% in patients and 43% in controls. TT was 12% in patients and 8% in controls. Allele frequency for C was noted to be 0.73 (patients) and 0.705 (controls), p-value (1). For T, 0.025 (patients) and 0.001(controls), p-value (0.88). The genotyping for DR4 gene 626 C>G polymorphism was done for 100 head and neck cancer patients and 100 age and sex matched healthy controls. All the genotypes for the polymorphism were in Hardy-Weinberg Equilibrium. For DR4626 C>G genotype, CC was 10% in patients and 2% in controls. GC was 63% in patients and 40% in controls. GG was 27% in patients and 58% in controls. Interestingly, in DR4 genotyping, CC was predisposing factor and GG acted as a protective factor. Allele frequency for C was noted to be 0.41 (patients) and 0.22 (controls), p-value (0.81). For G, 0.585 (patients) and 0.78 (controls), p-value (0.867). For the A1322G polymorphism, TT was 23% in patients and 36% in controls with a p-value 0.09 (table 6). CT was statistically significant in patients (45%) and controls (28%), p-value 0.04. CC was non-significant in patients (32%) and controls (36%), p-value 0.62 (table 6). C allele was 0.45% in patients and 0.5% in controls. T allele was 0.54% in patients and 0.5% in controls. Future studies must converge on somatic mutations, epigenetic mutations and expression analysis of TRAIL and DR4 to get a step closer to individualized medicine.

We have previously shown that complement component 3 (C3) is secreted by malignant epithelial cells. To understand the mechanism of upregulation of C3 expression in tumor cells, we studied the C3 promoter and identified that twist basic helix-loop-helix transcription factor 1 (TWIST1) binds to the C3 promoter and enhances its expression. Because TWIST1 mediates epithelial-mesenchymal transition (EMT), we studied the effect of C3 on EMT and found that C3 decreased E-cadherin expression on cancer cells and promoted EMT. We showed that C3-induced reduction in E-cadherin expression in ovarian cancer cells was mediated by C3a and is Krüppel-like factor 5 dependent. We investigated the association between TWIST1 and C3 in malignant tumors and in murine embryos. TWIST1 and C3 colocalized at the invasive tumor edges, and in the neural crest and limb buds of mouse embryos. Our results identified TWIST1 as a transcription factor that regulates C3 expression during pathologic and physiologic EMT.

Survivin and transcription factor p65 (NF‑κB p65) participate in the progression of esophageal squamous cell carcinoma (ESCC). However, the mechanism of NF‑κB p65 activation in ESCC remains to be elucidated. The aim of the present study was to investigate the role of survivin in the activation of NF‑κB p65 in ESCC. The expression levels of survivin, NF‑κB p65, inhibitor of nuclear factor κB kinase subunit α (IKKα) and inhibitor of nuclear factor κB kinase subunit β (IKKβ) were detected in ESCC tissue samples. Eca109 and KYSE150 cells were cultured and survivin activity was modulated via transfection with an overexpression plasmid, a small hairpin RNA plasmid and a specific inhibitor. Quantitative reverse transcription-polymerase chain reaction and western blotting assays were conducted to assess the effects of survivin on the expression levels of IKKα, IKKβ and NF‑κB p65. Cell cycle and apoptosis assays were conducted to detect surviving-dependent cellular behavior changes. In addition, the luciferase reporter gene assay and chromatin immunoprecipitation assay were conducted to determine the genomic sites responsible for surviving-induced activation of NF‑κB p65. The present study demonstrated that the expression of survivin is positively correlated with IKKα and IKKβ in ESCC tissues. Survivin affected the mRNA and protein expression levels of IKKα, IKKβ, and NF‑κB p65 in Eca109 and KYSE150 cells. Furthermore, survivin increased the transcriptional activity of the IKKβ promoter and bound to the IKKβ promoter region in the Eca109 cells. Downregulation of survivin arrested the cell cycle at the G2/M phase and induced apoptosis. Results of the present study suggest that survivin activates NF‑κB p65 in Eca109 cells via binding to the IKKβ promoter region and upregulating IKKβ promoter transcriptional activity. Survivin overexpression activates NF‑κB p65, which is important in the acquisition and maintenance of the oncogenic characteristics of ESCC.

Angiogenesis is a key factor in the growth and dissemination of malignant diseases, including breast cancer, with significant implications for its clinical management. It is known that microRNAs (miRNAs) play important roles in regulating tumor properties in cancers. However, whether miR-497 contributes to breast cancer angiogenesis remains unknown. Our study demonstrated that miR-497 was significantly downregulated in breast cancer tissue samples and cell lines. Conditioned medium obtained from breast cancer cell line MCF-7, treated with miR-497 mimics, suppressed the proliferation and tube formation of human umbilical vein endothelial cells in vitro, in comparison with the untransfected cells or cells transfected with the control vector alone. Furthermore, western blot assay confirmed that the overexpression of miR-497 reduced VEGF and HIF-1α protein levels. In addition, stable transfection of miR-497 inhibited tumorigenicity and angiogenesis in vivo. Moreover, HIF-1α was also increased in the breast cancer cells under a hypoxic condition, while the ectopic expression of miR-497 partially restored its level. Taken together, our findings indicate that miR-497 is a potential target for the biological therapy of breast cancer. Moreover, miR-497 inhibited the growth of tumors and reduced angiogenesis in a nude mouse xenograft tumor model, which was probably caused by the downregulation of pro-angiogenic molecules, such as VEGF and HIF-1α.

Although the tumor suppressive role of miR-101 is well documented in hepatocellular carcinoma (HCC), how the expression of miR-101 itself is regulated remains elusive. In the present study, we demonstrated that the miR-101 precursor pre-miR-101-1 could be regulated by an important epigenetic regulator, the enhancer of zeste homolog 2 (EZH2). Reporter gene assays revealed that ectopic expression of EZH2 inhibited the transcriptional activities of miR-101-1 promoter. Subsequent analyses revealed that miR-101-1 directly represses the expression of EZH2, and miR-101-1 and EZH2 form a reciprocal negative feedback loop as indicated by the fact that ectopic mature miR-101 could induce endogenous pre-miR-101-1 expression. This mature miR-101-induced pre-miR-101 expression was specific to pre-miR-101-1 and depended on EZH2 activities. Moreover, our results also demonstrated that similar antitumor effects can be achieved either by ectopic miR-101 or EZH2 silencing in HCC cells. These findings show that elevated EZH2 contributes to miR-101 deregulation in HCC and highlight the coordinated role of miR-101 and EZH2 in hepatocarcinogenesis.

Oral cell lines have provided valuable insights into the various molecular pathways in oral carcinogenesis. Several landmark studies in oral oncology have utilized commercially available normal, dysplastic and cancer cell lines to decode the genetic alterations leading to the development of oral cancer. Most of these studies have shown a significant degree of variation in their mutation landscapes. These variations were thought to represent the heterogeneity of oral cancer.(1) But in a recent study, Dickman et al have shown that normal and dysplastic cell lines carry specific genetic alterations within the parent cell line, thus questioning the authenticity of several published mutation profiles. These genetic alterations in the commercial cell lines have been attributed to several factors, the most common being immortalization. Normal and dysplastic cell lines unlike cancer cell lines attain senescence following limited number of replication. Immortalization of the normal and dysplastic cell lines would aid the researcher in maintaining a viable population of cells for further studies. Ideally, the immortalized cell line must possess potential for indefinite replication and must retain the genetic makeup of its parent cell line.(2).

MicroRNAs (miRNAs/miRs) are important regulators of multiple cellular processes, and their dysregulation is a common event in tumorigenesis, including the development of hepatocellular carcinoma (HCC). Studies have shown that certain miRNAs are associated with resistance to chemotherapy or drug sensitization; however, the underlying mechanisms have largely remained elusive. Multiple drug resistance is a major barrier for the treatment of advanced HCC. In the present study, miR-101 was observed to be downregulated in a panel of HCC cell lines, suggesting that it has a tumor suppressor role. Furthermore, transfection of miR-101 significantly enhanced the cytotoxicity of doxorubicin to HepG2 cells. While overexpression of miR-101 did not influence the accumulation of doxorubicin, it promoted the apoptosis-inducing effect of doxorubicin in HepG2 cells. A bioinformatics analysis predicted that miR-101 directly targeted the 3'-untranslated region of myeloid cell leukemia 1 (Mcl-1), which was verified by a luciferase reporter assay. Finally, transfection of HepG2 cells with Mcl-1 expression plasmid inhibited apoptosis caused by doxorubicin plus miR-101 expression. In conclusion, the present study showed that miR-101 is a negative regulator of Mcl-1 in HCC, and the combination of miR-101 expression with doxorubicin may represent a novel approach for the treatment of HCC.

Cysteine-rich C-terminal 1 (CRCT1) is encoded by the epidermal differentiation complex (EDC), a gene cluster that was recently linked to esophageal cancer. However, the role of CRCT1 in esophageal squamous cell cancer (ESCC) and the underlying mechanism remain unclear. In the present study, we show that CRCT1 is downregulated in ESCC in association with TNM stage and lymph node metastasis. Restoring CRCT1 in ESCC cells by lentivirus-mediated gene transfer inhibited cell proliferation and xenograft tumor formation. CRCT1 overexpression promoted ESCC cell apoptosis and upregulated the expression of apoptosis-related proteins. CRCT1 expression was inversely correlated with the levels of microRNA-520 g (miR-520 g) in ESCC tissues, and CRCT1 was identified as a direct target gene of miR-520 g in ESCC cells. Consistent with the effects of CRCT1 overexpression, knockdown of miR-520 g inhibited growth and induced apoptosis in ESCC cells. Our results suggest that CRCT1 functions as a tumor suppressor gene in ESCC and is regulated by miR-520 g, providing potential therapeutic targets for the treatment of ESCC.

The microRNA miR-452 has been shown to function as a tumor suppressor. However, the cellular mechanism and potential application of miR-452-mediated cancer suppression remain great unknown. This study aims to identify how miR-452 acts in regulating non-small cell lung cancer (NSCLC) proliferation and metastasis. Expression of miR-452 via adenoviral (Ad) vector inhibits the proliferation, invasion, and migration of NSCLC cells A549 or H460. Our data also shows that miR-452 down-regulates the expression of Bmi-1 as well as pro-survival or anti-apoptosis regulators Survivin, cIAP-1, and cIAP-2. By such gene interference, miR-452 modulates NSCLC cell epithelial-mesenchymal transition (EMT) and further disrupts their migration and invasion. Moreover, miR-452 blocks the activation of PI3K/AKT pathway, which is also required for EMT process. These data reveal that miR-452 treatment could be a novel target or strategy for NSCLC treatment.

Ovarian cancer is one of the most common human malignancies in women. MiR-214 and semaphorin 4D (sema 4D) were found to be abhorrently expressed and involved in the progress of several kinds of malignant cancers. This study is aimed to investigate the cellular role of miR-214 and demonstrate that miR-214 negatively regulated sema 4D in ovarian cancer cells. The data showed that miR-214 expression was consistently lower in ovarian cancer tissues and cells than those in the normal controls. Over-expression of miR-214 in ovarian cancer SKOV-3 cells inhibited cell proliferation and induced apoptosis. It was suggested that miR-214 functioned as the tumor suppressor in ovarian cancer. Bioinformatic analysis indicated that miR-214 possibly regulated sema 4D by binding the sema 4D messenger RNA (mRNA) 3'-untranslated region (UTR). Sema 4D mRNA and protein levels were up-regulated in ovarian cancer tissues and SKOV-3 cells. Up-regulation of miR-214 in SKOV-3 cell line suppressed the sema 4D expression in both protein and nucleic acid levels. While, down-regulation of miR-214 in SKOV-3 cells would increase sema 4D protein and nucleic acid expression levels. The effects of miR-214 up- and down-regulation on luciferase activities of wild-type (WT) sema 4D 3'-UTR were completely removed upon introduction of mutation in 3'-UTR of WT sema 4D. Therefore, the data also demonstrated that sema 4D was the direct target of miR-214 and was negatively regulated by miR-214 in ovarian cancer cells.

Osteosarcoma is the most common kind of primary bone tumors with high morbidity in infants and adolescents. While the molecular mechanism of osteosarcoma has gained considerable attention, the mechanisms underlying its initiation and progression remain unclear. Recent studies have discovered that long non-coding RNAs (lncRNAs) play an important role in multiply biological processes including cell development, differentiation, proliferation, invasion, and migration. Deregulated expression of lncRNAs has been found in cancers including osteosarcoma. This review summarized the deregulation and functional role of lncRNAs in osteosarcoma and their potential application for diagnosis and treatment of osteosarcoma.

Hodgkin's lymphoma (HL) is a malignant disease of the lymphatic system. The therapy has been improved during the last decades but there are still patients who cannot be cured, and the therapy is associated with several adverse late effects. Therefore, we asked which genes might be involved in the chemotherapy resistance of HL cells. We observed that HL cells became more resistant against cisplatin after treatment with cobalt chloride. Therefore, we analyzed which genes were differentially expressed between cells incubated in medium with or without cobalt chloride. We found several genes which were up- or downregulated in the presence of cobalt chloride and might be involved in the modulation of chemotherapy resistance. Cobalt chloride is a hypoxia-mimetic agent. Therefore, we tested chemo-resistance and gene expression of HL cells under hypoxic conditions and confirmed the results from the cobalt chloride experiments. Taken together, activation of the hypoxia pathway led to altered gene expression and drug resistance of HL cells. Differentially expressed genes might be interesting targets for the development of future treatment strategies against drug-resistant HL.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Cancer metastasis is a major obstacle in clinical cancer therapy. The mechanisms underlying the metastasis of HCC remain unclear. Glucose-regulated protein 94 (GRP94) is a key protein involved in mediating cancer progression, and it is highly expressed in HCC specimens. However, the role of GRP94 in cancer metastasis is unclear. A specific short hairpin RNA (shRNA) was employed to knock down GRP94 gene expression in HCC cell lines. Wound-healing migration, transwell migration, and invasion assays were performed to determine the migration and invasive ability of HCC cells. We demonstrated that silencing GRP94 inhibited HCC cell wound healing, migration, and invasion. Furthermore, our findings indicated that GRP94 knockdown might attenuate HCC cell metastasis by inhibiting CCT8/c-Jun/EMT signaling. Our study indicated that silencing GRP94 significantly reduced the migration and invasion abilities of HCC cells. Moreover, depleting GRP94 inhibited cell migration and invasion by downregulating CCT8/c-Jun signaling. Thus, our data suggest that the GRP94/CCT8/c-Jun/EMT signaling cascade might be a new therapeutic target for HCC.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been successfully used to treat patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, despite an initial excellent response, recurrence within one or two years is common. Diagnosis and treatment of leptomeningeal metastasis (LM), a form of NSCLC recurrence, remains particularly difficult. Here, we analyzed the EGFR mutation status of cerebrospinal fluid (CSF) directly using real-time polymerase chain reaction (PCR) and evaluated the efficacy of therapy with erlotinib, an EGFR TKI.

According to the 2012 statistics of the International Agency for Research on Cancer (IARC), gastric cancer is the fifth most common malignancy, and the third leading cause of cancer-related deaths worldwide. Conventional chemotherapy and radiation have shown limited efficacy for advanced gastric cancer, showing an overall survival (OS) rate of ~10 months. Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is the first approved molecularly targeted agent for HER2-overexpressing gastric cancer, which was found to prolong the OS and the progression-free survival (PFS) of patients. However, HER2 overexpression is present only in a minority of patients with gastric cancer. Hence, other targeted agents are urgently needed. Ramucirumab, a novel human IgG1 monoclonal antibody that selectively targets the extracellular domain of VEGF receptor 2 (VEGFR2), is regarded as a new standard second-line treatment for patients with advanced gastric cancer. The combination of two or more targeted agents directed against two different molecular targets may improve the survival of patients with advanced gastric cancer. Although great efforts have been made, the effect of targeted therapy for gastric cancer is limited. One key reason is that participants in clinical trials for new targeted agents were not selected by detection of the targeted molecule. Here, we review clinical trials related to molecular targets such as anti-epidermal growth factor receptor signaling including anti-HER2 and anti-EGFR1, anti-VEGF signaling, anti-mammalian target of rapamycin (mTOR), tyrosine kinase inhibitors (TKIs) and anti-MET.