Lack of ADAM2, CALR3 and SAGE1 Cancer/Testis Antigen Expression in Lung and Breast Cancer

Immunotherapy is emerging as a supplement to conventional cancer treatment, and identifying antigen targets for specific types of cancer is critical to optimizing therapeutic efficacy. Cancer/testis antigens are highly promising targets for immunotherapy due to their cancer-specific expression and antigenic properties, but the expression patterns of most of the more than 200 identified cancer/testis antigens in various cancers remain largely uncharacterized. In this study, we investigated the expression of the cancer/testis antigens ADAM2, CALR3 and SAGE1 in lung and breast cancer, the two most frequent human cancers, with the purpose of providing novel therapeutic targets for these diseases. We used a set of previously uncharacterized antibodies against the cancer/testis antigens ADAM2, CALR3 and SAGE1 to investigate their expression in a large panel of normal tissues as well as breast and lung cancers. Staining for the well-characterized MAGE-A proteins was included for comparison. Immunohistochemical staining confirmed previous mRNA analysis demonstrating that ADAM2, CALR3 and SAGE1 proteins are confined to testis in normal individuals. Negative tissues included plancenta, which express many other CT antigens, such as MAGE-A proteins. Surprisingly, we detected no ADAM2, CALR3 and SAGE1 in the 67 lung cancers (mainly non-small lung cancer) and 189 breast cancers, while MAGE-A proteins were present in 15% and 7–16% of these tumor types, respectively. Treatment with DNA methyltransferase inhibitors has been proposed as an attractive strategy to increase the expression of cancer/testis antigens in tumors before immunotargeting; however, neither ADAM2, CALR3 nor SAGE1 could be significantly induced in lung and breast cancer cell lines using this strategy. Our results suggest that ADAM2, CALR3 and SAGE1 cancer/testis antigens are not promising targets for immunotherapy of breast and lung cancer.     

LncRNA–CDC6 promotes breast cancer progression and function as ceRNA to target CDC6 by sponging microRNA-215

Rapid proliferation and metastasis of breast cancers resulted in poor prognosis in clinic. Recent studies have proved that long noncoding RNAs (lncRNAs) were involved in tumor progression. In this study, we aimed to determine the roles and mechanisms of lncRNA–cell division cycle 6 (CDC6) in regulating proliferation and metastasis of breast cancer. Clinically, lncRNA–CDC6 was highly expressed in tumor tissues and was positively correlated with clinical stages of breast cancers. Functionally, the ectopic expression of lncRNA–CDC6 promoted proliferation via regulation of G1 phase checkpoint, and further promoting the migration capability. Moreover, lncRNA–CDC6 could function as competitive endogenous RNA (ceRNA) via directly sponging of microRNA-215 (miR-215), which further regulating the expression of CDC6. Taken together, our results proved that lncRNA–CDC6 could function as ceRNA and promote the proliferation and metastasis of breast cancer cells, which provided a novel prognostic marker for breast cancers in clinic.     

LncRNA‐PAGBC acts as a microRNA sponge and promotes gallbladder tumorigenesis

Long noncoding RNAs (lncRNAs) play roles in the development and progression of many cancers; however, the contributions of lncRNAs to human gallbladder cancer (GBC) remain largely unknown. In this study, we identify a group of differentially expressed lncRNAs in human GBC tissues, including prognosis‐associated gallbladder cancer lncRNA (lncRNA‐PAGBC), which we find to be an independent prognostic marker in GBC. Functional analysis indicates that lncRNA‐PAGBC promotes tumour growth and metastasis of GBC cells. More importantly, as a competitive endogenous RNA (ceRNA), lncRNA‐PAGBC competitively binds to the tumour suppressive microRNAs miR‐133b and miR‐511. This competitive role of lncRNA‐PAGBC is required for its ability to promote tumour growth and metastasis and to activate the AKT/mTOR pathway. Moreover, lncRNA‐PAGBC interacts with polyadenylate binding protein cytoplasmic 1 (PABPC1) and is stabilized by this interaction. This work provides novel insight on the molecular pathogenesis of GBC.     

Analysis of gene expression profiles of gastric normal and cancer tissues by SAGE

In an attempt to understand the molecular bases of gastric cancer progression, we have analyzed the differentially expressed genes in gastric cancer by SAGE. Four SAGE cDNA tag libraries were constructed from two sets of gastric cancer and normal tissues and 241,127 tags were obtained. By comparing the tags from cancer and normal tissues, 414 differentially expressed tags, representing 383 genes, were identified in cancer tissues (p 相似文献   

Impaired expression of NER gene network in sporadic solid tumors

Nucleotide repair genes are not generally altered in sporadic solid tumors. However, point mutations are found scattered throughout the genome of cancer cells indicating that the repair pathways are dysfunctional. To address this point, in this work we focus on the expression pathways rather than in the DNA structure of repair genes related to either genome stability or essential metabolic functions. We present here a novel statistical analysis comparing ten gene expression pathways in human normal and cancer cells using serial analysis of gene expression (SAGE) data. We find that in cancer cells nucleotide-excision repair (NER) and apoptosis are the most impaired pathways and have a highly altered diversity of gene expression profile when compared to normal cells. We propose that genome point mutations in sporadic tumors can be explained by a structurally conserved NER with a functional disorder generated from its entanglement with the apoptosis gene network.     

The long non‐coding RNA SPRY4‐IT1: An emerging player in tumorigenesis and osteosarcoma

Accumulating evidence from genome‐wide analysis and functional studies has begun to unveil the important role of long non‐coding RNAs (lncRNAs) in cancer development. The lncRNA SPRY4‐IT1 is derived from an intron of SPRY4 gene and was originally reported to be upregulated in melanoma in which it functioned as an oncogene. Since this discovery, an increasing number of studies have investigated the expression and function of SPRY4‐IT1 in human cancers. Aberrant expression of SPRY4‐IT1 has now been documented in different cancer types, including osteosarcoma, breast, renal, oesophageal and prostate cancers. However, its deregulation and function in lung and gastric cancers remain controversial. Pertinent to clinical practice, SPRY4‐IT1 expression has been shown to predict survival of cancer patients. In this review, we summarize recent evidence concerning SPRY4‐IT1 deregulation and the associated mechanisms in human cancers. We also discuss the potential clinical utilization of this lncRNA as a diagnostic and prognostic biomarker for cancer patients.     

Long noncoding RNA MIR155HG facilitates pancreatic cancer progression through negative regulation of miR-802

Long noncoding RNAs (lncRNAs) present the key regulatory functions in tumorigenesis. More and more studies have suggested that lncRNA MIR155HG is involved in different human cancers. However, the underlying regulatory role of lncRNA MIR155HG and potential mechanisms in pancreatic cancer (PC) remain illusive. In this research, our group found that lncRNA MIR155HG expression was remarkably increased in PC tumor tissue and cells compared to that in the adjacent normal tissue and cells. In addition, higher MIR155HG expression was positively associated with the poor prognosis of patients. In addition, we exhibited that silence of MIR155HG by short hairpin RNA knockdown significantly inhibited cell growth and promoted cell apoptosis in PC cells. We performed bioinformatics analysis to search for the target of MIR155HG. As demonstrated by Luciferase reporter assay, we found that miR-802, a tumor suppressor in various cancer, is a direct target of MIR155HG. We demonstrated that the tumor-promoting effects of MIR155HG were contributed by negative regulation of miR-802 in PC cells. In summary, our results suggest that lncRNA MIR155HG might be applied as a novel diagnostic and therapeutic target for PC.     

Characterization of NADPH oxidase 5 expression in human tumors and tumor cell lines with a novel mouse monoclonal antibody

Reactive oxygen species generated by NADPH oxidase 5 (Nox5) have been implicated in physiological and pathophysiological signaling pathways, including cancer development and progression. However, because immunological tools are lacking, knowledge of the role of Nox5 in tumor biology has been limited; the expression of Nox5 protein across tumors and normal tissues is essentially unknown. Here, we report the characterization and use of a mouse monoclonal antibody against a recombinant Nox5 protein (bp 600–746) for expression profiling of Nox5 in human tumors by tissue microarray analysis. Using our novel antibody, we also report the detection of endogenous Nox5 protein in human UACC-257 melanoma cells. Immunofluorescence, confocal microscopy, and immunohistochemical techniques were employed to demonstrate Nox5 localization throughout UACC-257 cells, with perinuclear enhancement. Tissue microarray analysis revealed, for the first time, substantial Nox5 overexpression in several human cancers, including those of prostate, breast, colon, lung, brain, and ovary, as well as in malignant melanoma and non-Hodgkin lymphoma; expression in most nonmalignant tissues was negative to weak. This validated mouse monoclonal antibody will promote further exploration of the functional significance of Nox5 in human pathophysiology, including tumor cell growth and proliferation.     

Influence of the transposable element neighborhood on human gene expression in normal and tumor tissues

Transposable elements (TEs) are genomic sequences able to replicate themselves, and to move from one chromosomal position to another within the genome. Many TEs contain their own regulatory regions, which means that they may influence the expression of neighboring genes. TEs may also be activated and transcribed in various cancers. We therefore tested whether gene expression in normal and tumor tissues is influenced by the neighboring TEs. To do this, we associated all human genes to the nearest TEs. We analyzed the expression of these genes in normal and tumor tissues using SAGE and EST data, and related this to the presence and type of TEs in their vicinity. We confirmed that TEs tend to be located in antisense orientation relative to their hosting genes. We found that the average number of tissues where a gene is expressed varies depending on the type of TEs located near the gene, and that the difference in expression level between normal and tumor tissues is greatest for genes that host SINE elements. This deregulation increases with the number of SINE copies in the gene vicinity. This suggests that SINE elements might contribute to the cascade of gene deregulation in cancer cells.     

LncRNA DANCR promotes cervical cancer progression by upregulating ROCK1 via sponging miR-335-5p

Emerging evidence highlights the key regulatory roles of long noncoding RNAs (lncRNAs) in the initiation and progression of numerous malignancies. The lncRNA identified as differentiation antagonizing nonprotein coding RNA (DANCR) is a novel lncRNA widely involved in the development of multiple human cancers. However, the function of DANCR and its potential molecular mechanism in cervical cancer remain unclear. In this study, we discovered that DANCR was significantly elevated in cervical cancer tissues and cells, and was closely correlated with poor prognosis of cervical cancer patients. In addition, knockdown of DANCR inhibited proliferation, migration, and invasion of cervical cancer cells in vitro, indicating that DANCR functioned as an oncogene in cervical cancer. Moreover, we verified that DANCR could directly bind to miR-335-5p, isolating miR-335-5p from its target gene Rho-associated coiled-coil containing protein kinase 1 (ROCK1). Functional analysis showed that DANCR regulated ROCK1 expression by competitively binding to miR-335-5p. Further cellular behavioral experiments revealed that miR-335-5p mimics and ROCK1 knockdown reversed the effects of upregulated DANCR on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of cervical cancer cells by rescue assays. In summary, this study demonstrated that DANCR promoted cervical cancer progression by functioning as a competing endogenous RNA (ceRNA) to regulate ROCK1 expression via sponging miR-335-5p, suggesting a novel potential therapeutic target for cervical cancer.