Xiaobo Guo

Down-regulation of miR-622 in gastric cancer promotes cellular invasion and tumor metastasis by targeting ING1 gene

AIM To evaluate the biological and clinical characteristics of miR-622 in gastric cancer. METHODS We analyzed the expression of miR-622 in 57 pair matched gastric neoplastic and adjacent non-neoplastic tissues by quantitative real-time polymerase chain reaction. Functional analysis of miR-622 expression was assessed in vitro in gastric cancer cell lines with miR-622 precursor and inhibitor. The roles of miR-622 in tumorigenesis and tumor metastasis were analyzed using a stable miR-622 expression plasmid in nude mice. A luciferase reporter assay was used to assess the effect of miR-622 on inhibitor of growth family, member 1 (ING1) expression. RESULTS Expression of miR-622 was down-regulated in gastric cancer. MiR-622 was found involved in differentiation and lymphatic metastasis in human gastric cancer. Ectopic expression of miR-622 promoted invasion, tumorigenesis and metastasis of gastric cancer cells both in vitro and in vivo. ING1 is a direct target of miR-622. CONCLUSION These findings help clarify the molecular mechanisms involved in gastric cancer metastasis and indicate that miR-622 modulation may be a bona fide treatment of gastric cancer.

Identification of microRNAs associated with lymphangiogenesis in human gastric cancer

PurposeLymphatic metastasis is a primary cause of gastric cancer-related death, yet factors governing tumor cell lymphatic metastasis have not been fully elucidated. MicroRNAs (miRNAs) are a recently discovered class of regulatory, non-coding RNAs, some of which are involved in gastric cancer progression. However, little is known about which miRNA contributes to the lymphatic metastasis in human gastric cancer. This prompted us to find the significant miRNAs associated with lymphangiogenesis in human gastric cancer.MethodsWe screened vascular endothelial growth factor C (VEGF-C) expression in several gastric cancer cell lines as well as in the immortalized human gastric mucosal cell line GES-1, by real-time reverse transcriptase PCR (qRT-PCR). The gastric cancer cell lines MKN-45 and SGC-7901, which have commonly been cultured with human lymphatic endothelial cells (HLECs) in vitro, promoted tube formation of HLECs following transformation with a VEGF-C expression vector. Using microarrays, we identified a panel of differentially expressed miRNAs in HLECs that had been co-cultured with VEGF-C-transformed gastric cancer cells compared with non-transformed gastric cancer cells. A subset of miRNAs was further validated using qRT-PCR.ResultsWe found altered expression of miRNAs in HLECs co-cultured with lymphangiogenesis-inducing VEGF-C-transformed gastric cancer cells, with 47 up-regulated and 42 down-regulated miRNAs. These findings were confirmed by qRT-PCR of selected miRNAs. Furthermore, several miRNAs were differentially expressed in patients with positive lymphatic metastasis of the primary gastric tumor. Up-regulated miRNAs included miR-648, miR-5002-3p, miR-4754, miR-4760-5p, miR-4491, miR-4252, miR-5007-3p, and miR-647; and down-regulated miRNAs included miR-3178, miR-593-5p, miR-4485, miR-135a-3p, miR-17, miR-1469, and miR-124-5p.ConclusionsSeveral lymphangiogenesis-related miRNAs are significantly altered during lymphatic metastasis of gastric cancer.

VEZT, a Novel Putative Tumor Suppressor, Suppresses the Growth and Tumorigenicity of Gastric Cancer

Vezatin (VEZT), an adherens junctions transmembrane protein, was identified as a putative tumor suppressor in our previous study. However, the role of VEZT in tumorigenesis remains elusive. We aimed to clarify its epigenetic regulation and biological functions in gastric cancer. In this study, we show that the expression level of VEZT is involved in lymphatic metastasis, depth of cancer invasion and TNM stage in 104 gastric cancer patients. Bisulfate sequencing polymerase chain reaction (BSP) methods showed that VEZT was hypermethylated in tissues and corresponding blood of gastric cancer patients compared with healthy controls. Helicobacter pylori (H. pylori) infection induces the methylation and silencing of VEZT in GES-1 cells. Restoring VEZT expression in MKN-45 and NCI-N87 gastric cancer cells inhibited growth, invasion and tumorigenesis in vitro and in vivo. Global microarray analysis was applied to analyze the molecular basis of the biological functions of VEZT after VEZT transfection combined with real-time PCR and chromatin immunoprecipitation assay. G protein-coupled receptor 56(GPR56), cell growth, cell division cycle 42(CDC42), migration/invasion and transcription factor 19(TCF19), cell cycle progression, were identified as direct VEZT target genes. TCF19, a novel target of VEZT, was functionally validated. Overexpression of TCF19 in MKN-45 cells increased cell cycle progress and growth ability. This study provides novel insight into the regulation of the VEZT gene, which could represent a potential target for therapeutic anti-cancer strategies.

Long noncoding RNAs as potential biomarkers in gastric cancer: Opportunities and challenges.

Gastric cancer (GC) is a major threat to human health, and its prognosis is poor due to the lack of appropriate biomarkers. LncRNAs are a group of non-protein-coding RNAs that regulate gene expression at the transcriptional or posttranscriptional level. LncRNAs play essential roles in GC initiation and development in the same way as oncogenes or tumour suppressor genes. Recent investigations have revealed that lncRNAs are often aberrantly expressed in GC; are involved in cell proliferation, apoptosis, migration and invasion; and correlate with the malignant phenotype of GC. LncRNAs, especially the lncRNAs present in the blood and gastric juice, show potential value as biomarkers for the diagnosis of GC or for determining disease prognosis. However, there are still many challenges to be faced before lncRNAs can be used in clinical applications. In this review, we summarise lncRNAs as the potential biomarkers for GC and the current challenges associated with the clinical application.

Long noncoding RNA OR3A4 promotes metastasis and tumorigenicity in gastric cancer

The contribution of long noncoding RNAs (lncRNAs) to metastasis of gastric cancer remains largely unknown. We used microarray analysis to identify lncRNAs differentially expressed between normal gastric tissues and gastric cancer tissues and validated these differences in quantitative real-time (qRT)-PCR experiments. The expression levels of lncRNA olfactory receptor, family 3, subfamily A, member 4 (OR3A4) were significantly associated with lymphatic metastasis, the depth of cancer invasion, and distal metastasis in 130 paired gastric cancer tissues. The effects of OR3A4 were assessed by overexpressing and silencing OR3A4 in gastric cancer cells. OR3A4 promoted cancer cell growth, angiogenesis, metastasis, and tumorigenesis in vitro and in vivo. Global microarray analysis combined with RT-PCR, RNA immunoprecipitation, and RNA pull-down analyses after OR3A4 transfection demonstrated that OR3A4 influenced biologic functions in gastric cancer cells via regulating the activation of PDLIM2, MACC1, NTN4, and GNB2L1. Our results reveal OR3A4 as an oncogenic lncRNA that promotes tumor progression, Therefore, lncRNAs might function as key regulatory hubs in gastric cancer progression.

Roles of long non-coding RNAs in gastric cancer metastasis

Gastric cancer is the second leading cause of cancer-related deaths. Metastasis, which is an important element of gastric cancer, leads to a high mortality rate and to a poor prognosis. Gastric cancer metastasis has a complex progression that involves multiple biological processes. The comprehensive mechanisms of metastasis remain unclear, though traditional regulation modulates the molecular functions associated with metastasis. Long non-coding RNAs (lncRNAs) have a role in different gene regulatory pathways by epigenetic modification and by transcriptional and post-transcription regulation. lncRNAs participate in various diseases, including Alzheimers disease, cardiovascular disease, and cancer. The altered expressions of certain lncRNAs are linked to gastric cancer metastasis and invasion, as with tumor suppressor genes or oncogenes. Studies have partly elucidated the roles of lncRNAs as biomarkers and in therapies, as well as their gene regulatory mechanisms. However, comprehensive knowledge regarding the functional mechanisms of gene regulation in metastatic gastric cancer remains scarce. To provide a theoretical basis for therapeutic intervention in metastatic gastric cancer, we reviewed the functions of lncRNAs and their regulatory roles in gastric cancer metastasis.

The Diagnostic Efficacy and Biological Effects of microRNA-29b for Colon Cancer

Background: Colorectal cancer is one of the most common cancers worldwide in terms of both incidence and mortality. The associations of expressions of tissue and plasma miR-29b were not detected in this study. Methods: There are 400 healthy age- and gender-matched controls enrolled in this study in a rate of 1:2. The receiver operating characteristic curve analysis was undertaken using the expression level for miR-29b in the colorectal cancer specimens from patients with cancer and healthy controls to assess the diagnostic accuracy of both tissue and plasma miR-29b levels. Results: It was found that the expression of plasma miR-29b is associated with the tissue miR-29b. Advanced study showed that aberrant miR-29b expression in both cancer tissues and plasma is associated with the clinicopathological data of patients with colorectal cancer. Tissue miR-29b showed an AUC of 0.883, with a sensitivity of 81.6% and a specificity of 84.9%. However, the AUC for plasma miR-29b was 0.743, with a sensitivity of 61.4% and a specificity of 72.5%. The analyses of the biological effects of miR-29b for colorectal cancer showed that miR-29b could inhibit the cell viability and migration. Conclusion: In summary, our data suggest that both the tissue and the plasma miR-29b levels have some value as a diagnostic tool for colorectal cancer. Advanced biological effects were conducted to detect the potential effect on the cell viability and migration. Future investigations including larger patient populations and patients with early-stage colorectal cancer are needed to confirm the potential diagnostic value of miRNA-29b in colorectal cancer.

Expression of tumor necrosis factor α-induced protein 8 is upregulated in human gastric cancer and regulates cell proliferation, invasion and migration.

Tumor necrosis factor α-induced protein 8 (TNFAIP8) has been associated with the tumorigenicity of various types of cancer, however, the expression of TNFAIP8 and its function in gastric cancer remain to be fully elucidated. Therefore, the present study examined the expression and biological function of TNFAIP8 in gastric cancer. The expression levels of TNFAIP8 were determined in 86 gastric cancer tissue samples and adjacent normal tissues using immunohistochemistry, and in four gastric cancer cell lines and GES-1 cells using reverse transcription-quantitative polymerase chain reaction. The expression of TNFAIP8 and its association with the tumor, node, metastasis (TNM) status and lymphatic metastasis of gastric cancer was evaluated. Furthermore, the functions of decreased expression levels of TNFAIP8 were analyzed in human gastric cancer cell lines. The expression of TNFAIP8 was significantly upregulated in the gastric cancer tissues and in the gastric cancer cell lines, and its expression levels were associated with the TNM staging and lymphatic metastasis. Furthermore, decreased expression of TNFAIP8 inhibited the growth, invasion and migration of gastric cancer cells. These data provided an innovative insight suggesting the downregulation of TNFAIP8 as a meaningful approach for treating human gastric cancer and other types of cancer. In addition, the expression levels of TNFAIP8 may be considered as a biomarker of gastric cancer progression.

Fibroblast growth factor receptor 4 as a potential prognostic and therapeutic marker in colorectal cancer

Abstract The purpose of the study was to explore the significance of FGFR4 protein expression in colorectal cancer. Immunohistochemistry showed 46.8% (148/316) tumors positive for FGFR4 and 7.3% (23/316) for adjacent normal specimens. FGFR4 positivity was correlated with shortened disease free survival (DFS) and overall survival (OS). Multivariate analysis revealed that FGFR4 was an independent prognostic factor. FGFR4 silencing markedly reduced the migration and invasion capacity of colorectal cancer cell lines. These results suggest FGFR4 is a potential prognostic and therapeutic marker for colorectal cancer.

Long noncoding RNA C21orF96 promotes the migration, invasion and lymph node metastasis in gastric cancer

Lymphatic metastasis is a primary cause of gastric cancer-related death, yet factors governing tumor cell lymphatic metastasis have not been fully elucidated. Little is known about the contributions of long noncoding RNAs (lncRNAs) to lymphatic metastasis in gastric cancer. Differentially expressional lncRNAs between metastatic lymph node tissues and normal lymph node tissues were identified and validated by microarray and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Our results found that the expression level of C21orF96 was over-expressed in positive lymph node tissues and gastric cancer tissues. We evaluated the altered expressions of C21orF96 in gastric cancer tissues comparing to adjacent normal specimens, and their association with clinicopathological factors. We showed that the expression levels of C21orF96 were associated with gross appearance, lymphatic metastasis and distal metastasis. The effect of C21orF96 was assessed by over-expressing the lncRNA. We also found that C21orF96 promoted the tubular formation, migration and invasion. Together, our results suggest that C21orF96 is an oncogenic lncRNA that promotes tumor progression and plays a pivotal role in the development of gastric cancer.