Jian Guan

MiR-141 Suppresses the Migration and Invasion of HCC Cells by Targeting Tiam1

Background We have demonstrated that T lymphoma invasion and metastasis 1 (Tiam1) gene is associated with the poor prognosis of patients with hepatocellular carcinoma (HCC), and we used a computational approach to identify miR-141 as a Tiam1-targeting microRNA (miRNA). Here, we explored the function of miR-141 and the relationship between miR-141 and Tiam1 gene in HCC. Methods The miR-141 expression in HCC tissues and cell lines was detected and its roles in regulation of HCC cell proliferation, migration and invasion and target gene expression was investigated. Tiam1 was identified as a novel target of miR-141. Ethics statement: our study was approved by the Nanfang Hospital Medical Ethics Committee Ethics statement. Written informed consent was obtained before collection. Results Based on in situ hybridization (ISH) analysis, miR-141 was down-regulated in the same HCC samples. Kaplan-Meier analysis demonstrated that patients with low miR-141 expression had poorer overall survival rate than that of the patients with high miR-141 expression. Furthermore, multivariate Cox regression analysis indicated that miR-141 could serve as an independent prognostic factor in HCC. MiR-141 significantly inhibited in vitro cell proliferation, migration and invasion as proved by gain- and loss- of function studies, while the mRNA and protein levels of Tiam1 were reduced in cells over-expressing miR-141. Moreover, Tiam1 treatment antagonized this effect, while knockdown of Tiam1 by Tiam1 short hairpin RNA (shTiam1) induced inhibitory effects. Conclusions These findings indicated that miR-141 functions as a tumor suppressor and inhibits the migration and invasion of HCC cells by targeting Tiam1, which may provide novel prognostic and treatment strategies for HCC patients.

Tiam1 is associated with hepatocellular carcinoma metastasis

We have previously demonstrated that overexpression of T lymphoma invasion and metastasis 1 (Tiam1) is correlated with poor prognosis in patients with hepatocellular carcinoma (HCC). In this study, we tried to further investigate the potential roles of Tiam1 in the progression of HCC in a larger set of samples. By detecting Tiam1 expression in 213 HCC patients, we observed that Tiam1 had a higher probability of being overexpressed in HCC patients with metastasis than those without metastasis (68.3% vs. 52.7%, p = 0.036). In addition, the cell line with high metastatic potential expressed more Tiam1 than did the cell line with low metastatic potential. Overexpression of Tiam1 was suggested to be significantly correlated with HCC metastasis. We stably upregulated Tiam1 expression in MHCC97L as well as knocked down Tiam1 expression in HCCLM6. We also investigated the effects of Tiam1 overexpression and knockdown on HCC cells proliferation, migration and invasion in vitro and on tumorigenicity and metastasis in vivo. Overexpression of Tiam1 increased proliferation, migration and invasion of MHCC97L cells, while knockdown of Tiam1 in HCCLM6 cells resulted in the reverse. In vivo functional studies showed upregulation of Tiam1 expression led to an enhancement of tumorigenicity and metastatic potential in mice. However, knockdown of Tiam1 expression exhibited nearly 2.2‐fold retardation in tumor growth and great inhibition on tumor metastases. Our results indicate that Tiam1, as a metastasis‐related gene, may contribute to HCC invasion and metastasis, and consequently, it may be a useful biomarker for therapeutic strategy and control in HCC treatment.

Tiam1, overexpressed in most malignancies, is a novel tumor biomarker

T lymphoma invasion and metastasis 1 (Tiam1) is a guanine nucleotide exchange factor (GNEF) family member, and is considered to be involved in many important cellular processes and oncogenesis. In this study, we investigated Tiam1 expression differences between normal tissue and malignant tissue using tissue microarray (TMA), and further studied the Tiam1 mRNA and protein level in 9 hepatoma lines. Forty-nine tumor tissue and 47 normal tissue samples were detected via TMA by immunohistochemistry with polyclonal antibody. Tiam1 expression in 9 human hepatoma cell lines, namely Huh-7, HepG2, Hep3B, SMMC-7721, QGy-7701, QGy-7703, BEL-7402, BEL-7404 and BEL-7405, and 1 normal primary human hepatocyte, HL-7702, was compared by means of fluorescence quantitative PCR, immunocytochemistry assay and Western blotting. We found that Tiam1 was significantly expressed in various malignancies. Tiam1 mRNA and protein levels were significantly elevated in the 9 human hepatoma cell lines compared to the normal primary human hepatocyte. Our results suggest that Tiam1 overexpression in malignant neoplasms could be a novel effective supplementary biomarker for tumors, including hepatocellular carcinoma.

18F-FDG PET/CT evaluation of lymphoma with renal involvement: comparison with renal carcinoma.

Objective: Lymphoma can arise at any anatomic site, but it is rare to find kidney involvement. The aim of this study was to assess the role of 18F-flourodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in detecting lymphoma with renal involvement. Reports of such use of 18F-FDG PET/CT are limited. Methods: Twelve lymphoma patients with renal involvement and 12 renal carcinoma patients were studied with 18F-FDG PET/CT. Intense 18F-FDG uptake, suggestive of positivity, was measured in mean standardized uptake values (standardized uptake values [SUV] mean). Results: The results of PET/CT were validated by bone marrow, biopsy tissue and/or surgery. 18F-FDG PET/CT detected lymphoma with renal involvement lesions or renal carcinoma lesions in at least one site in the 24 patients. 18F-FDG uptake by the lymphoma lesions was much higher than the 18F-FDG uptake by the renal clear cell carcinomas (SUV mean 6.37 ± 2.28 vs 2.58 ± 0.62), and similar to that of renal cell carcinoma and renal collecting duct carcinoma (SUV mean 6.37 ± 2.28 vs 6.27 ± 1.15). There were dissimilar morphological changes in the homologous CT. Differing from renal cancer, lymphoma in the spleen, uterus, and bone marrow can easily be diagnosed by 18F-FDG PET/CT. Conclusion: The lesions of lymphoma with renal involvement, and especially those of primary renal lymphoma, are 18F-FDG avid. PET/CT appears to be useful in comparing these lesions with those of renal carcinoma, especially for primary renal lymphoma.

A meta-analysis comparing cisplatin-based to carboplatin-based chemotherapy in moderate to advanced squamous cell carcinoma of head and neck (SCCHN)

Purpose This study was performed to compare the efficacies and toxicities of cisplatin (CDDP)- and carboplatin (CBDCA)-based chemotherapy (CT) in patients with SCCHN. Methods The search strategy included Pubmed, Science Direct, the Cochrane Library, and the China National Knowledge Internet Web. Statistical analyses were performed using RevMan 5.2. The primary endpoint was overall survival (OS) with secondary endpoints of locoregional control (LRC) and grade≥3 toxicity. Results Overall, 12 studies and 1165 patients were included. CDDP-based CT significantly improved 5-year OS (HR=0.67, 95% CI, 0.49 to 0.91; P=0.01) compared to the CBDCA group. No difference in the 3-year OS/LRC was observed, but a subgroup analysis showed a better 3-year OS in the CDDP arm for non-nasopharynx carcinoma (non-NPC) SCCHN (HR=0.66, 95% CI, 0.48 to 0.91; P=0.01). The CDDP-based CT was associated with more gastrointestinal toxicities (RR=4.58; P=0.005) and nephrotoxicity (4/110=3.6%) compared to the CBDCA group, but fewer anemia, leukopenia and thrombocytopenia with RRs of 0.27, 0.71, and 0.28 respectively. Conclusions Patients with CDDP-based CT can achieve a higher OS, but there is no significant difference in LRC. The CDDP-based CT is associated with fewer hematological toxicities but more gastrointestinal toxicities and nephrotoxicity compared to the CBDCA arm.

A meta-analysis of weekly cisplatin versus three weekly cisplatin chemotherapy plus concurrent radiotherapy (CRT) for advanced head and neck cancer (HNC)

Purpose This study was performed to compare the efficacies and acute toxicities in weekly- and three weekly- cisplatin based concurrent chemoradiotherapy (CCRT) for advanced HNC patients. Results 779 patients of 10 studies were eligible. No difference in the 2-, 3-year OS or 1-, 2-year LRFS was observed, whereas patients in three weekly CCRT arm tended to have a better 5-year OS (HR=1.79, 95%C 0.97-3.31, p=0.06). Weekly arm seemed to show less gastrointestinal toxicities (RR=0.59, 95%CI 0.34-1.02, p=0.06), but similar hematologic toxicity compared to three weekly arm. Subgroup analysis displayed more grade ≥3 mucositis (RR=1.72, p=0.01), and more chemotherapy related delay/interrupt (RR=2.68, p<0.0001) in weekly arm for non-nasopharynx carcinoma (non-NPC) HNC. Methods We conducted the meta-analysis by searching PubMed, MEDLINE, ScienceDirect, Cochrane Library and China National Knowledge Infrastructure (CNKI) databases. The primary endpoint was overall survival (OS) with secondary endpoints locoregional recurrence-free survival (LRFS) and grade≥3 acute adverse events. RevMan 5.2 was used to perform statistical analyses. Conclusions Three weekly cisplatin-based CCRT might achieve a higher long-term OS with no significant difference in a shorter OS and LRFS. Weekly arm was associated with less gastrointestinal toxicities but more grade≥3 mucositis and chemotherapy related delay/interrupt. Large randomized trials were urgent to further define superiority of these two regimens.

The MDM2 309 T/G polymorphism is associated with head and neck cancer risk especially in nasopharyngeal cancer: a meta-analysis.

Background: Published data on the association between mouse double minute 2 (MDM2) 309 T/G single nucleotide polymorphism (SNP) and head and neck cancer (HNC) risk are inconclusive. To derive a more precise estimation of the relationship, we performed a meta-analysis. Material and Methods: A systematic computerized search of PubMed was performed. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association between the polymorphism and HNC risk. The pooled ORs were performed for TT versus GG, TG versus GG, dominant model (TT+TG vs. GG) and recessive model (TT vs. TG+GG), respectively. Results: A total of 9 studies including 2,755 cases and 4,121 controls were involved in the final meta-analysis. The results of the overall meta-analysis provided some evidence of an association between the polymorphism and HNC risk (OR = 0.82, 95% CI 0.67–0.99 for TG vs. GG). In the subgroup meta-analysis based on the types of tumor, we detected a significantly decreased NPC risk for all genetic models. Conclusion: This meta-analysis suggests that the GG genotype of MDM2 SNP309 is associated with HNC risk. The MDM2 SNP309G allele is a highly penetrant risk factor for developing NPC.

18F-FDG uptake for prediction EGFR mutation status in non-small cell lung cancer.

AbstractEpidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) are a response to EGFR-tyrosine kinase inhibitor. However, a lack of sufficient tumor tissue has been a limitation for determining EGFR mutation status in clinical practice. The objective of this study was to predict EGFR mutation status in NSCLC patients based on a model including maximum standardized uptake value (SUVmax) and clinical features.We retrospectively reviewed NSCLC patients undergoing EGFR mutation testing and pretreatment positron emission tomography/computed tomography between March 2009 and December 2013. The relationships of EGFR mutations with both SUVmax and patient characteristics were evaluated, and a multivariate logistic regression analysis was performed. The model was assessed by area under the receiver-operating characteristic curve (AUC) and was prospectively validated during January to June 2014.Three hundred and sixteen patients meeting the criteria were enrolled for model construction. The SUVmax values were significantly lower for EGFR mutations (mean, 9.5 ± 5.74) than for EGFR wild-type (mean, 12.7 ± 6.43; P < 0.001). ROC curve analysis showed that the SUVmax cutoff point was 8.1, for which the AUC was 0.65 (95% confidence interval [CI], 0.60–0.72). In addition, multivariate analysis also showed that low SUVmax (⩽8.1) was a predictor of EGFR mutations, for which the AUC was 0.77, combining nonsmoking history and primary tumor size (⩽5 cm). Eighty-five patients were enrolled to validate the predictive model, and the overall accuracy, sensitivity, and specificity were 77.6%, 64.6% (95% CI 40.7–82.8), and 82.5% (95% CI 70.9–91.0), respectively.The specific FDG uptake value could be considered to effectively predict EGFR mutation status of NSCLC patients by considering smoking history and primary tumor size when genetic tests are not available.