Tiantian Zhen

MACC1 down-regulation inhibits proliferation and tumourigenicity of nasopharyngeal carcinoma cells through Akt/β-catenin signaling pathway.

The present study was aimed at investigating the expression of metastasis-associated in colon cancer 1 (MACC1) in nasopharyngeal carcinoma (NPC), its relationship with β-catenin, Met expression and the clinicopathological features of NPC, and its roles in carcinogenesis of NPC. Our results showed that MACC1 expression was higher in NPC cells and tissues than that in normal nasopharyngeal cells and chronic inflammation of the nasopharynx tissues, respectively. MACC1 expression was closely related to the clinical stage (p = 0.005) and the N classification (p<0.05) of NPC. Significant correlations between MACC1 expression and Met expression (p = 0.003), MACC1 expression and β-catenin abnormal expression (p = 0.033) were found in NPC tissues. MACC1 knockdown dramatically inhibited cellular proliferation, migration, invasion, and colony formation, but induced apoptosis in NPC cells compared with the control group. Furthermore, MACC1 down-regulation inhibited phosphorylated-Akt (Ser473) and β-catenin expression in NPC cells, but phosphorylated-Erk1/2 expression was not altered. Further study showed that phosphotidylinsitol-3-kinase inhibitor downregulated β-catenin and Met expression in NPC cells. There was a significant relationship between MACC1 expression and phosphorylated-Akt expression (p = 0.03), β-catenin abnormal expression and phosphorylated-Akt expression (p = 0.012) in NPC tissue, respectively. In addition, Epstein Barr virus-encoded oncogene latent membrane protein 1 upregulated MACC1 expression in NPC cells. Our results firstly suggest that MACC1 plays an important role in carcinogenesis of NPC through Akt/β-catenin signaling pathway. Targeting MACC1 may be a novel therapeutic strategy for NPC.

Clinical and biological significance of miR-378a-3p and miR-378a-5p in colorectal cancer

To investigate miR-378a-3p and miR-378a-5p expression and their relationships with the clinicopathological features of colorectal cancer (CRC). Our results showed that miR-378a-3p and miR-378a-5p expression were dramatically lower in CRC cell lines and tissues than that in adjacent normal colorectal mucosal tissues, respectively. MiR-378a-3p and miR-378a-5p expression were significantly associated with histological differentiation and TNM stage, respectively. CRC patients with low miR-378a-3p and miR-378a-5p expression had a significantly shorter survival time than those patients with high miR-378a-3p and miR-378a-5p expression (p<0.001, p<0.001), respectively. Univariate and multivariable Cox regression analysis showed that tumour size, TNM stage, miR-378a-3p expression and miR-378a-5p expression were independent prognostic factors for CRC patients. Ectopic miR-378a-3p or miR-378a-5p expression inhibited cellular proliferation and colony formation, induced apoptosis and G1-phase cell cycle arrest in CRC cells, but had no effect on migration and invasion of CRC cells. Furthermore, miR-378a-3p over-expression or down-regulation could inhibit or enhance insulin-like growth factor 1 receptor (IGF1R) expression in CRC cells. There was a significantly negative correlation between IGF1R protein expression and miR-378a-3p expression in CRC tissues. MiR-378a-3p over-expression or down-regulation suppressed or enhanced phosphorylated-ERK1/2 protein level, but had no effect on phosphorylated-Akt protein level. In conclusion, miR-378a-3p and miR-378a-5p expression might play an important role as tumour suppressor gene in the initial stage of carcinogenesis of CRC.

Clinical and biological significance of hepatoma‐derived growth factor in Ewing's sarcoma

We sought to investigate the clinicopathological significance and biological function of hepatoma‐derived growth factor (HDGF) in Ewings sarcoma. Our results showed that HDGF expression is up‐regulated in Ewings sarcoma. Nuclear HDGF expression is significantly associated with tumour volume (p < 0.001), metastases at diagnosis (p < 0.001), low overall survival rate (p < 0.001) and low disease‐free survival rate (p < 0.001). HDGF knock‐down results in significant reduction of Ewings sarcoma cell growth, proliferation and enhances tumourigenesis, both in vitro and in vivo. Meanwhile, HDGF knock‐down causes cell cycle arrest and enhanced sensitization to serum starvation‐induced apoptosis. Furthermore, recombinant HDGF promotes proliferation and colony formation of Ewings sarcoma cells. Ninety‐eight candidate HDGF downstream genes were identified in Ewings sarcoma cells using cDNA microarray analysis. In addition, we found that HDGF knock‐down inhibited FLI1 expression in Ewings sarcoma cells at the mRNA and protein levels. Our findings suggest that HDGF exhibits oncogenic properties and may be a novel prognostic factor in Ewings sarcoma. Targeting HDGF might be a potential therapeutic strategy for Ewings sarcoma. Copyright

Clinicopathological features of inflammatory pseudotumour‐like follicular dendritic cell tumour of the abdomen

Inflammatory pseudotumour‐like follicular dendritic cell (FDC) tumour is an extremely rare neoplasm. Herein, we report 10 cases of inflammatory pseudotumour‐like FDC tumours in the abdomen and analyse their clinicopathological features.

p53 and hepatoma-derived growth factor expression and their clinicopathological association with Ewing family tumour

Purpose To investigate p53 and hepatoma-derived growth factor (HDGF) expression and their association with clinicopathological features of Ewing family tumour (EFT). Experimental design A total of 108 cases of EFT were retrospectively analysed. p53 and HDGF expression were detected using immunohistochemistry, and the relationships between p53 expression and HDGF expression and clinicopathological features of EFT were analysed. Kaplan–Meier curves were applied to estimate overall survival, log-rank test was used to assess prognostic relevance of p53 expression with overall survival and Cox regression model was performed to evaluate HRs. Results p53 expression and high HDGF expression was found in 17 (15.7%) and 55 (50.9%) patients, respectively. p53 expression was significantly associated with metastatic stage at initial diagnosis (p=0.007) and tumour venous/nerve invasion (p=0.023). A significant positive correlation was found between p53 expression and HDGF expression in EFT (p=0.022). p53 expression was an independent prognostic factor for overall survival of patients with EFT (p<0.001). Patients with p53-positive/high HDGF expression had a significantly shorter overall survival than those with p53-positive/low HDGF expression or p53-negative/high HDGF expression or p53-negative/low HDGF expression. We first constructed a novel molecular staging system by combining p53 expression and HDGF expression, which significantly improved prognostic stratification for patients with EFT. Conclusions p53 expression was an independent prognostic factor for patients with EFT. Combining p53 expression and HDGF expression significantly improved prognostic stratification for patients with EFT.

Positive feedback loop of hepatoma-derived growth factor and β-catenin promotes carcinogenesis of colorectal cancer

To clarify the role of hepatoma-derived growth factor (HDGF) and β-catenin in carcinogenesis of colorectal cancer (CRC), our results showed that high HDGF expression was found in CRC cells and tissues and significantly related to histological differentiation (p = 0.035) and lymph node metastasis (p = 0.000). Significant positive correlation between HDGF expression and β-catenin abnormal expression was found in CRC tissues. High HDGF and lymph node metastasis were the strong independent prognostic indicators for reduced overall survival in CRC patients. HDGF knockdown dramatically inhibited cellular proliferation, migration, invasion, and tumorigenesis, both in vitro and in vivo, but induced G1 phase arrest and apoptosis in CRC cells. HDGF knock-down dramatically suppressed β-catenin and its down-stream genes expression in CRC cells. Intriguingly, β-catenin knock-down dramatically suppressed HDGF expression in CRC cells. Human recombinant Wnt3a and DKK1 treatment increased and decreased HDGF, β-catenin, c-Myc, cyclin D1, MMP9, and phos-GSK-3β (Ser9) protein expression in nuclear and cytoplasmic fraction of CRC cells upon β-catenin knock-down, respectively. Three HDGF-binding elements in β-catenin promoter were found and specific for transcriptional activation of β-catenin in CRC cells. In conclusion, our results first suggest that HDGF and β-catenin interacts as a positive feedback loop, which plays an important role in carcinogenesis and progression of CRC.

Multifocal epithelioid angiosarcoma of the jejunum: a case report

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Genomic variation of Epstein–Barr virus in inflammatory pseudotumour‐like follicular dendritic cell tumour

Sir: Inflammatory pseudotumour-like follicular dendritic cell (FDC) tumour is a rare neoplasm characterized by the proliferation of spindle to ovoid tumour cells showing morphological and immunophenotypical features of FDC with intense lymphoplasmacytic infiltrate. The tumour almost invariably involves the spleen or liver and is associated consistently with Epstein–Barr virus (EBV) infection. According to the sequence divergence of the EBNA-3 gene, EBV has two distinct strains, subtypes A and B. In addition, based on alignment to the EBV prototype B95-8 cell genome, several variants of EBV have been identified, such as the type ‘f’ variant with an additional BamHI restriction site (nucleotide: 55 718, GGATAC?GGATCC) at the BamHI-F region, loss of the XhoI restriction endonuclease site induced by a missense point mutation at nucleotide 169 425 (nucleotide sequence: 169 423–169 428; GAGCTC? GATCTC) in exon 1 of the LMP1 gene and 30 base pairs (bp) deleted-LMP1 (del-LMP1) within nucleotide sequence 168 341–168 322 and amino acid positions 346–355 in exon 3 of LMP1. Herein, we first analysed the EBV strain subtype and its genomic variation in 11 cases of inflammatory pseudotumourlike FDC tumour from Guangzhou, Southern of China, where nasopharyngeal carcinoma is endemic. As shown in Figure 1 and Table 1, all 11 cases (100%, 11 of 11) were EBV strain subtype A with a 153 bp amplification product. The result indicates that inflammatory pseudotumour-like FDC tumour is ethnically or geographically correlated, because all our cases were from Guangzhou, where the EBV strain subtype A is predominant. The EBV type ‘f’ variant was found in 63.6% (seven of 11) cases and type F was found in two cases (cases 9 and 11). It was interesting that two cases (cases 5 and 7) were both type F and ‘f’ variant which had three fragments of 198 bp, 127 bp and 71 bp. Cheng et al. have reported that the EBV type F was predominant in EBV-associated gastric lymphoepithelioma-like carcinoma from southern China. The frequency of the EBV type ‘f’ variation might be related to a different tumour type. Only eight cases were amplified successfully, except cases 1, 5 and 10. Our results showed that only one case (case 4) was XhoI loss variant. Five cases (cases 2, 6, 7, 8 and 9) were XhoI wild-type. However, one case (case 3) was both XhoI wild-type and XhoI loss variant. Cheng et al. have reported that the EBV XhoI loss variant is predominant in EBV-associated gastric

miR-27a-3p targeting RXRα promotes colorectal cancer progression by activating Wnt/β-catenin pathway

This study aimed to elucidate how miR-27a-3p modulates the Wnt/β-catenin signaling pathway to promote colorectal cancer (CRC) progression. Our results showed that the expression of miR-27a-3p was up-regulated in CRC and closely associated with histological differentiation, clinical stage, distant metastasis and CRC patients’ survival. miR-27a-3p mimic suppressed apoptosis and promoted proliferation, migration, invasion of CRC cells in vitro and in vivo. Whereas miR-27a-3p inhibitor promoted apoptosis and suppressed proliferation, migration, invasion of CRC cells in vitro and in vivo. Furthermore, RXRα was the target gene of miR-27a-3p in CRC. miR-27a-3p expression negatively correlated with RXRα expression in CRC tissues. The underlining mechanism study showed that miR-27a-3p/RXRα/Wnt/β-catenin signaling pathway is involved in CRC progression. In conclusion, our findings first demonstrate that miR-27a-3p is a prognostic and/or potential therapeutic biomarker for CRC patients and RXRα as miR-27a-3p targeting gene plays an important role in activation of the Wnt/β-catenin pathway during CRC progression.

The interaction of hepatoma-derived growth factor and β-catenin promotes tumorigenesis of synovial sarcoma

To clarify the clinicopathological and biological role of hepatoma-derived growth factor (HDGF) and β-catenin in synovial sarcoma. Our results showed that histological type and HDGF/β-catenin expression were the two important independent prognostic factors for overall survival in synovial sarcoma patients. HDGF knockdown dramatically inhibited cellular proliferation, colony formation, and migration but induced G1 phase arrest and apoptosis in SW982 cells. Recombinant HDGF enhanced synovial sarcoma cell growth and partially retrieved the cell growth suppression in SW982 cells upon HDGF knockdown. HDGF knockdown dramatically suppressed β-catenin and its downstream gene expression in SW982 cells. Intriguingly, β-catenin knockdown dramatically suppressed HDGF expression in SW982 cells. A direct interaction of HDGF and β-catenin was found in SW982 cells. Three HDGF-binding elements in β-catenin promoter were found and specific for transcriptional activation of β-catenin in SW982 cells. In conclusion, our findings first indicate that the interaction of HDGF and β-catenin may play a crucial role in tumorigenesis of synovial sarcoma.