[Show abstract][Hide abstract] ABSTRACT: Here, we report the characterization of a candidate tumor suppressor gene leucine-rich glioma inactivated 1 (LGI1) in human esophageal squamous cell carcinoma (ESCC). Downregulation of LGI1 has been detected in approximately 50% of primary
ESCCs, which was significantly associated with advanced clinical stage (P < 0.001), lymph node metastasis (P < 0.001), tumor invasion (P = 0.009) and poor disease-specific survival (P < 0.001). Functional studies found that LGI1 could inhibit cell growth, clonogenicity, cell motility and tumor formation
in nude mice. Mechanistic investigations suggested that LGI1 acted through extracellular signal-regulated kinase (ERK1/2)
signaling to downregulate matrix metalloproteinase (MMP)-3 expression and subsequently suppressed tumor metastasis. Taken
together, our study revealed that LGI1 plays an important tumor suppressive role in the development and progression of ESCC,
with possible application in clinics as a biomarker and a potential new therapeutic target.
[Show abstract][Hide abstract] ABSTRACT: Gastric cancer remains one of the leading causes of cancer death worldwide. Patients usually present late with local invasion or metastasis, for which there are no effective therapies available. Following previous studies that identified the adhesion molecule Cadherin-17(CDH17) as a potential marker for gastric carcinoma, we performed proof-of-principle studies to develop rational therapeutic approaches targeting CDH17 for treating this disease.
Immunohistochemistry was used to study the expression of CDH17 in 156 gastric carcinomas, and the relationship between survival and CDH17 expression was studied by multivariate analyses. The effect of RNA interference-mediated knockdown of CDH17 on proliferation of gastric carcinoma cell lines was examined in vitro and in vivo, as well as the effects on downstream signaling by immunoblotting.
CDH17 was consistently up-regulated in human gastric cancers, and overall survival in patients with CDH17 upregulation was poorer than in those without expression of this gene (5 yrs overall survival rate 29.0% vs. 45.0%, P<0.01). Functional assays demonstrated that CDH17 knockdown inhibited cell proliferation, adhesion, migration, invasion, clonogenicity and induce G0/G1 arrest. In mice, shRNA-mediated CDH17 knockdown markedly inhibits tumor growth; intratumoral injection of CDH17 shRNAs results in significant antitumor effects on transplanted tumor models. The antitumor mechanisms underlying CDH17 inhibition involve inactivation of Wnt/β-catenin signaling.
Our results identify CDH17 as a biomarker of gastric carcinoma and attractive therapeutic target for this aggressive malignancy.
PLoS ONE 03/2013; 8(3):e56959. DOI:10.1371/journal.pone.0056959 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with significantly high prevalence in Southern China. Unlike other head and neck cancers, mutations or deletions of tumor suppressor genes (TSGs) in NPC are not common. Recently, down-regulation of TSGs expression by microRNA (miRNA) is increasingly recognized as an important mechanism of nasopharyngeal tumorigenesis. In this study, we reported that microRNA-144 (miR-144) was frequently up-regulated in NPC specimens and cell lines. Repression of miR-144 significantly decreased cell proliferation, clonogenicity, migration, invasion and tumor formation in nude mice, while restoring miR-144 in miR-144 attenuated NPC cells exhibited a strong tumorigenic role. Further, we found that miR-144 was inversely correlated with the tumor suppressor gene Phosphatase and tensin homolog (PTEN) in NPC specimens and cell lines, and then we identified PTEN as a direct target of miR-144 in NPC cell lines. PTEN down-regulation in miR-144 attenuated cells could increase cell growth, migration and invasion. Mechanistic investigations revealed that miR-144 suppressed the expression of PTEN to increase the expression of pAkt and cyclin D1 to promote G1-phase transition and decrease E-cadherin to promote migration and invasion. Taken together, we provide compelling evidence that miR-144 functions as an onco-miRNA in NPC, and its onco-effects are mediated chiefly by repressing PTEN expression to activate the PI3K/Akt pathway.
[Show abstract][Hide abstract] ABSTRACT: Deletion of the short arm of chromosome 3 is one of the most frequent genetic alterations in many solid tumors including nasopharyngeal carcinoma (NPC), suggesting the existence of one or more tumor suppressor genes (TSGs) within the frequently deleted region. A putative TSG RBMS3 (RNA binding motif, single stranded interacting protein 3), located at 3p24-p23, has been identified in our previous study. Here, we reported that downregulation of RBMS3 was detected in 3/3 NPC cell lines and 13/15 (86.7%) primary NPC tissues. Functional studies using both overexpression and suppression systems demonstrated that RBMS3 has a strong tumor suppressive role in NPC. The tumor suppressive mechanism of RBMS3 was associated with its role in cell cycle arrest at the G1/S checkpoint by upregulating p53 and p21, downregulating cyclin E and CDK2, and the subsequent inhibition of Rb-ser780. Further analysis demonstrated that RBMS3 had a pro-apoptotic role in a mitochondrial-dependent manner via activation of caspase-9 and PARP. Finally, RBMS3 inhibited microvessel formation, which may be mediated by down-regulation of MMP2 and β-catenin and inactivation of its downstream targets, including cyclin-D1, c-Myc, MMP7, and MMP9. Taken together, our findings define a function for RBMS3 as an important tumor suppressor gene in NPC.
PLoS ONE 09/2012; 7(9):e44636. DOI:10.1371/journal.pone.0044636 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nasopharyngeal carcinoma (NPC) is among the most common malignancies in southern China. Deletion of genomic DNA, which occurs during the complex pathogenesis process for NPC, represents a pivotal mechanism in the inactivation of tumor suppressor genes (TSGs). In many circumstances, loss of TSGs can be detected as diagnostic and prognostic markers in cancer. The short arm of chromosome 3 (3p) is a frequently deleted chromosomal region in NPC, with 3p21.1-21.2 and 3p25.2-26.1 being the most frequently deleted minimal regions. In recent years, our research group and others have focused on the identification and characterization of novel target TSGs at 3p, such as RASSF1A, BLU, RBMS3, and CHL1, in the development and progression of NPC. In this review, we summarize recent findings of TSGs at 3p and discuss some of these genes in detail. A better understanding of TSGs at 3p will significantly improve our understanding of NPC pathogenesis, diagnosis, and treatment.
Chinese journal of cancer 02/2012; 31(5):215-22. DOI:10.5732/cjc.011.10364 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interaction between neoplastic and stromal cells plays an important role in tumour progression. It was recently found that WNT2 was frequently overexpressed in fibroblasts isolated from tumour tissue tumour fibroblasts (TF) compared with fibroblasts from non-tumour tissue normal fibroblasts in oesophageal squamous cell carcinoma (OSCC). This study aimed to investigate the effect of TF-secreted Wnt2 in OSCC development via the tumour-stroma interaction.
Quantitative PCR, western blotting, immunohistochemistry and immunofluorescence were used to study the expression pattern of Wnt2 and its effect on the Wnt/β-catenin pathway. A Wnt2-secreting system was established in Chinese hamster ovary cells and its conditioned medium was used to study the role of Wnt2 in cell proliferation and invasion.
Expression of Wnt2 could only be detected in TF but not in OSCC cancer cell lines. In OSCC tissues, Wnt2(+) cells were mainly detected in the boundary between stroma and tumour tissue or scattered within tumour tissue. In this study, Wnt2-positive OSCC was defined when five or more Wnt2(+) cells were observed in 200× microscopy field. Interestingly, Wnt2-positive OSCC (22/51 cases) was significantly associated with lymph node metastases (p=0.001), advanced TNM stage (p=0.001) and disease-specific survival (p<0.0001). Functional study demonstrated that secreted Wnt2 could promote oesophageal cancer cell growth by activating the Wnt/β-catenin signalling pathway and subsequently upregulated cyclin D1 and c-myc expression. Further study found that Wnt2 could enhance cell motility and invasiveness by inducing epithelial-mesenchymal transition.
TF-secreted Wnt2 acts as a growth and invasion-promoting factor through activating the canonical Wnt/β-catenin signalling pathway in oesophageal cancer cells.
Gut 06/2011; 60(12):1635-43. DOI:10.1136/gut.2011.241638 · 14.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to assess the value of metastatic lymph node ratio in predicting prognosis of patients with stage III colorectal cancer.
From 2000 to 2005 inclusively, a total of 626 patients featuring stage III colorectal cancer underwent curative resection. These patients were stratified into LNR groups: 1 (0 < LNR ≤ 0.1); 2 (0.1 < LNR ≤ 0.25); 3 (0.25 < LNR ≤ 0.5); and 4 (LNR > 0.5). The follow-up was closed in April 2010. Kaplan-Meier survival curve and log-rank test were used to evaluate the prognostic value of LNR. A Cox regression model was used for multivariate analyses.
With a median follow-up period of 42.2 months, 5-year overall survival for groups LNR1, LNR2, LNR3, and LNR4 was 73%, 64%, 44%, and 22%, respectively. In the multivariate analysis, the LNR was an independent prognostic factor for survival (P < 0.001). LNR remained statistically significant (P < 0.001), both in patients with colon and rectum cancer regardless of the number of lymph nodes retrieved (≥12 or < 12). The survival rate of ratio group LNR1 was better than ratio group LNR4 (P < 0.001) for patients with the same IIIB or IIIC staging.
LNR is an accurate prognostic method for patients with stage III colorectal cancer. We proposed an algorithm to incorporate LNR into current AJCC staging system to form new staging.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effect of hepatitis B virus (HBV) infection on liver metastasis of colorectal cancer.
A total of 1298 colorectal cancer patients were recruited from January 2001 to March 2005 in this study. Enzyme-linked immunosorbent assay was used to test serum HBV markers for colorectal cancer. Patients were divided into study (infection) group and control (non-infection) group. Clinical features of patients in two groups were compared.
Liver metastasis was found in 319 out of the 1298 colorectal cancer patients. The incidence of liver metastasis was significantly lower in study group than in control group (14.2% vs 28.2%, P < 0.01). HBV infection significantly decreased the risk of liver metastasis [hazard ratio (HR): 0.50, 95% confidence interval (95% CI): 0.38-0.66], but the incidence of extrahepatic metastasis was significantly higher in study group than in control group (31.9% vs 17.0%, P < 0.01). The HR was the lowest in chronic hepatitis B group (HR: 0.29, 95% CI: 0.12-0.72). The number of liver metastatic lesions was significantly less in study group than in control group with a higher surgical resection rate. However, no significant difference was found in survival rate between the two groups (P = 0.95).
HBV infection decreases the risk of liver metastasis in patients with colorectal cancer and elevates the surgical resection rate of liver metastatic lesions.
World Journal of Gastroenterology 02/2011; 17(6):804-8. DOI:10.3748/wjg.v17.i6.804 · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the prognostic value of chromosome 18q microsatellite alterations (MA) in stage II colon cancer.
One hundred and six patients with sporadic stage II colon cancer were enrolled in this study. DNA was extracted from formalin-fixed, paraffin-embedded tumor and adjacent normal mucosal tissue samples. MA, including loss of heterozygosity (LOH) and microsatellite instability (MSI), was analyzed by polymerase chain reaction, polyacrylamide gel-electrophoresis and DNA sequencing at 5 microsatellite loci on chromosome 18q (D18S474, D18S55, D18S58, D18S61 and D18S64).
Among the 102 patients eligible for MA information, the overall frequencies of LOH, high and low frequency MSI/microsatellite stable were 49.0%, 17.6% and 82.4%, respectively. The high frequency of 18q-LOH was significantly associated with the poor 5-year overall survival (OS) (P = 0.008) and disease free survival (P = 0.006). High levels of MSI were significantly associated with a longer 5-year OS (P = 0.045) while the higher frequency of 18q-LOH at the loci of D18S474 and D18S61 was significantly associated with a poorer 5-year OS (P = 0.010 and 0.005, respectively). But multivariate analysis showed that only the frequency of 18q-LOH was significantly associated with the prognosis of the disease.
High frequency of 18q-LOH is an independent prognostic factor indicating poor prognosis of the patients with stage II colon cancer.
World Journal of Gastroenterology 12/2010; 16(47):6026-34. DOI:10.3748/wjg.v16.i47.6026 · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Estrogen receptor beta (ERβ) is the most highly expressed protein in patients with colon cancer. Matrix metalloproteinase 7 (MMP7) is consistently expressed throughout cancer progression. We have previously shown that endocrine therapy can inhibit MMP7 expression in colon cancer cells. In this study, we aim to identify the prognostic effects and correlation of ERβ and MMP7 in the context of colon cancer. ERβ and MMP7 levels were assessed by immunohistochemistry in normal mucosa and tumoral tissues from 423 patients with stage I-III colon cancer. The Cox proportional hazards regression model was applied to analyze the lifetime data, including overall survival (OS) and cause-specific survival (CSS). The 5-year survival rate was significantly higher in patients with high expression of nuclear ERβ than in patients with low expression (84.3% vs. 63.9%, respectively, p < 0.05). High expression of MMP7 was related to decreased OS (72% vs. 90%, respectively, p = 0.008) and 5-year survival (86.6% vs. 88.8%, respectively, p = 0.005) compared to patients with low expression of MMP7. In the subset of patients with high expression levels of tumoral nuclear ERβ, high expression of MMP7 was related to OS and CSS among colon cancer patients with high expression of ERβ. In conclusion, our results suggest that low expression of ERβ was a risk factor in colon cancer, and high expression of MMP7 was an independent prognostic factor of ERβ-positive patients with colon cancer.
[Show abstract][Hide abstract] ABSTRACT: Aimed to assess the relationship between H.Pylori and the clinicopathological features and prognosis of gastric cancer by quantitative detection of H.Pylori.
157 patients were enrolled, all patients had a record of clinicopathological parameters. Specimens including the tumor and non-neoplastic were detected for H.Pylori by Real-Time PCR and analyzed clinical data retrospectively. Variables independently affecting prognosis were investigated by means of multivariate analysis using the Cox proportional hazards model.
H.Pylori infection was greater in non-neoplastic tissue than the tumor tissue (p < 0.05), H.Pylori infection and its copies were related to the tumor site and N staging (p < 0.05). Overall survival (OS) in all 157 patients has no correlation with the H.Pylori infection status (p = 0.715). As to the patients who underwent a curative surgery, relapse-free survival (RFS) has no correlation with the H.Pylori infection status (p = 0.639). Among the H.Pylori positive patients, OS and RFS of those with higher copies were longer than in patients with low copies, but there was no significant statistical difference.
H.Pylori infection status and its copies were related to N staging. The OS and RFS in patients with positive H.Pylori status has no significant difference from the patients with negative H.Pylori status.
BMC Cancer 07/2010; 10(1):374. DOI:10.1186/1471-2407-10-374 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Many studies have shown that colon cancer is an estrogen-dependent carcinoma. This study explored the efficacy of endocrine therapy in colon cancer cells with high metastatic potential (HT29). We investigated the proliferation of HT29 cells after exposure to endocrine therapy (tamoxifen) and 5-FU.
Apoptosis was evaluated using flow cytometry. The expression of matrix metalloproteinases 7 (MMP-7) and estrogen receptor beta (ERbeta) was measured by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. The migration capability of treated cells was determined with wound scratch assay.
Tamoxifen alone, 5-FU alone, and the combination of the two drugs can significantly inhibit HT29 cell proliferation and migration, block the cells in G2/M phase and induce cell apoptosis. These drugs also can down-regulate MMP7 and ERbeta expression.
Our findings suggest that endocrine therapy is an efficient therapy for inhibiting ERbeta-positive colon cancer cell proliferation and migration via down-regulation of MMP7.
Journal of Experimental & Clinical Cancer Research 09/2009; 28(1):132. DOI:10.1186/1756-9966-28-132 · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The therapeutic effects of chemotherapy for malignant neoplasms are still unsatisfactory. This study was to evaluate the chemosensitivity of colorectal cancer tissues to therapeutic agents using histoculture drug response assay (HDRA), and explore the correlation of chemosensitivity to the expression levels of multidrug resistance (MDR) genes and proteins.
Twenty-two specimens of colorectal cancer were collected. The inhibition rates of single agents, including epirubicin, cisplatin (DDP), oxaliplatin, 5-FU, taxetere, irinotecan, and combinations of these agents, including 5-FU+epirubicin+DDP, 5-FU+irinotecan, 5-FU+oxaliplatin, 5-FU+taxetere+ DDP on colorectal cancer tissues were evaluated by HDRA. The agent whose inhibition rate was greater than 30% was considered sensitive, and the sensitivity was calculated. mRNA and protein levels of MDR genes and proteins in colorectal cancer tissues were measured by RT-PCR and immunohistochemistry.
Among the single agents, the inhibition rate of oxaliplatin (17.5%) and sensitivity of cancer tissues to 5-FU (36.4%) were the highest. In the combination groups of agents, the inhibition rate of 5-FU+ oxaliplatin (54.1%), and sensitivity of cancer tissues to 5-FU+epirubicin+DDP (71.4%) and to 5-FU+taxetere+DDP (71.4%) were the highest. The inhibition rates of and sensitivity of cancer tissues to combined agents were higher than those of single agents (P<0.05). Expressions of MDR1, multidrug resistance protein-1 (MRP1), ABC-binding cassette transporter superfamily-G-2 (ABCG2) mRNA were detected in 88.9%, 55.6% and 55.6% of specimens respectively; while those of MDR1, MRP1 and ABCG2 proteins were detected in 55.6%, 33.3%, and 50.0% of specimens respectively. Expressions of mRNA and proteins had no correlation in MDR1, MRP1 and ABCG2 (P>0.05). High expression of ABCG2 protein was correlated to the resistance of colorectal cancer cells to epirubicin (P<0.05).
Expressions of MDR proteins are correlated to chemosensitivity of colorectal cancer to some extents. By combining HDRA with measurement of MDR genes and proteins, chemosensitivity of individual tumors may be predicted to guide selection of effective chemotherapeutic agents.
Ai zheng = Aizheng = Chinese journal of cancer 09/2009; 28(9):932-8. DOI:10.5732/cjc.008.10787 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The therapeutic effects of chemotherapy on gastric cancer are still unsatisfactory. Predicting chemosensitivity of tumors as therapeutic guidance could help to improve the efficacy of chemotherapy. This study was to evaluate the chemosensitivity of gastric cancer to single or combined therapeutic agents by histoculture drug response assay, to evaluate the expression levels of multidrug resistance (MDR) genes and proteins and analyze their correlations to the chemosensitivity of gastric cancer.
The inhibitory effects of single agents, including epirubicin, cisplatin (DDP), oxaliplatin, 5-fluorouracil (5-FU), taxetere, irinotecan, and combined regimens, including 5-FU, epirubicin plus DDP, 5-FU plus irinotecan, 5-FU plus oxaliplatin, and 5-FU, taxetere plus DDP, on 22 specimens of gastric cancer were evaluated by histoculture drug response assay. The mRNA and protein expression of MDR1, MRP1 and ABCG2 in gastric cancer were detected by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry.
The inhibition rate of gastric cancer by 5-FU (29.8%) and sensitivity of gastric cancer to 5-FU (50.0%) were the highest among single agents; the inhibition rate of gastric cancer by 5-FU, taxetere plus DDP (59.8%) and sensitivity to 5-FU, epirubicin plus DDP (77.3%) were the highest among combined regimens; combined regimens achieved higher inhibition rate and sensitivity as compared with single agents (P<0.05). The positive rates of MDR1, MRP1, and ABCG2 mRNA were 90.9%, 54.5%, and 77.3%; the positive rates of MDR1, MRP1, and ABCG2 proteins were 36.4%, 54.5%, and 36.4%. High expression of MDR proteins in gastric cancer was related with the resistance to epirubicin (P<0.05).
High expression of MDR1, MRP1, ABCG2 proteins in gastric cancer is related with the resistance to epirubicin, which indicates that these MDR genes may play a role in conferring the drug resistance to epirubicin.
Ai zheng = Aizheng = Chinese journal of cancer 05/2009; 28(4):337-43. · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Studies have shown that estrogen receptor beta (ERbeta), which is highly expressed in colorectal cancer, is related to tumor metastasis. Matrix metalloproteinase (MMP)-7 is overexpressed in colorectal cancer, and plays an important role in tumor invasion and metastasis. This study was to explore the effect of tamoxifen (TAM) on apoptosis and MMP-7 expression in ERbeta-positive human colorectal cancer cell line HT-29.
After exposure to TAM, the proliferation of HT-29 cells was detected by MTT assay; cell apoptosis was evaluated using flow cytometry; expressions of ERbeta and MMP-7 were measured by Western blot.
TAM significantly inhibited cell growth of HT-29 in a time (24 h, 48 h, 72 h )-and dose (0, 10(-7), 10(-6), 10(-5),0 10(-4) mol/L )-dependent manner. TAM exposure caused significant cell apoptosis of HT-29 cells at the concentration of 10(-4) mol/L [(69.9+/-4.2)%]. Moreover, TAM could bind to ERbeta to down-regulate MMP-7 protein expression in HT-29 cells.
High concentration of TAM can inhibit the proliferation of ERbeta-positive HT-29 cells, and effectively bind with ERbeta to down-regulate MMP-7 expression.
Ai zheng = Aizheng = Chinese journal of cancer 11/2008; 27(11):1172-6. · 2.16 Impact Factor