Wensheng Qiu

MiR‐200b expression in breast cancer: a prognostic marker and act on cell proliferation and apoptosis by targeting Sp1

MicroRNAs (miRNAs) have been identified as important post‐transcriptional regulators involved in various biological and pathological processes of cells. In the present study, we investigated the roles and mechanisms of miR‐200b in human breast cancer (BC). MiR‐200b expression was carried out by qRT‐PCR in human BC cell lines and clinical samples and the prognostic potential of miR‐200b expression was further evaluated. In vitro, effects of miR‐200b on BC cell proliferation, apoptosis and cell cycle distribution were tested by CCK‐8 kit, flow cytometric analysis respectively. Luciferase assay and Western blot analysis were performed to validate the potential targets of miR‐200b after the preliminary screening by employing open access software. We found that miR‐200b was significantly down‐regulated in both BC tissues and cell lines. The low expression of miR‐200b was correlated with late TNM stage, negative oestrogen receptor and positive HER‐2 status. Multivariate analysis showed that miR‐200b expression was an independent prognostic predictor for BC patients. Integrated analysis identified Sp1 as a direct and functional target of miR‐200b. Knockdown of Sp1 inhibited cell proliferation, induce apoptosis and act on cell cycle resembling that of miR‐200b high expression. Our data demonstrates that miR‐200b has potential to serve as prognostic biomarker and tumour suppressor for BC patients. As a direct and functional target of miR‐200b, Sp1 and miR‐200b both could be an exciting target for BC treatment strategy.

FOXM1 mediates resistance to docetaxel in gastric cancer via up‐regulating Stathmin

Docetaxel is commonly used as an effective chemotherapeutic drug for gastric cancer patients recently. With the increasing emergence of docetaxel resistance nowadays, identification of suitable biomarkers for predicting chemosensitivity to docetaxel may be a key role for improving therapeutic effects for gastric cancer patients. In this study, we investigated the correlation between the expression of transcription factor forkhead box protein M1 (FOXM1) and chemotherapy response to docetaxel in gastric cancer, the possible mechanism for which was further explored. As a result, FOXM1 overexpression was shown to mediate resistance to docetaxel in gastric cancers. It altered microtubule dynamics to protect tumour cells from docetaxel‐induced apoptosis. Mechanistic investigations revealed that tubulin‐destabilizing protein Stathmin, which mediated docetaxel resistance in FOXM1‐silenced gastric cancer cells, is a direct down‐stream target of FOXM1, whereas another microtubule dynamics protein mitotic centromere–associated kinesin (MCAK), shown to be related to docetaxel resistance in gastric cancer cells, is not associated with FOXM1 expression significantly. These results were further provided by immunohistochemical analysis, indicating that FOXM1 and Stathmin expression levels were correlated in 103 post‐operational gastric cancer specimens. Moreover, when we attenuated FOXM1 expression with FOXM1 inhibitor thiostrepton, docetaxel resistance in gastric cancers was found to be reversed, simultaneously with the down‐regulation of FOXM1 and Stathmin. Therefore, FOXM1 can be a useful marker for predicting and monitoring docetaxel response. Through the inhibition of FOXM1, docetaxel resistance can be reversed, and thus FOXM1 could be a new therapeutic target in docetaxel‐resistant gastric cancer.

miR-141 confers docetaxel chemoresistance of breast cancer cells via regulation of EIF4E expression

Resistance to docetaxel, a chemotherapy drug for breast cancer (BC) treatment, occurs in ~50% of patients, and the underlying molecular mechanisms of drug resistance are not fully understood. Gene regulation through miR-141 has been proven to play an important role in cancer drug resistance. The present study investigated the role of miR-141 expression in BC cells of acquired docetaxel resistance. Inhibition of miR-141 enhanced the response to docetaxel in docetaxel-resistant cells (MCF-7/DTX and MDA-MB-231/DTX, respectively), whereas overexpression of miR-141 confered resistance in docetaxel-sensitive cells (MCF-7 and MDA-MB-231, respectively). By directly targeting the eukaryotic translation initiation factor 4E (EIF4E) mRNA, miR-141 acts on genes that are necessary for drug induced apoptosis rendering the cells drug resistant. Modulation of miR-141 expression was correlated with EIF4E expression changes and a direct interaction of miR-141 with EIF4E was shown by a luciferase assay. Thus, the present study is the first to show an increased expression of miR-141 in an acquired model of docetaxel resistance in BC. This serves as a mechanism of acquired docetaxel resistance in BC cells, possibly through direct interactions with EIF4E, therefore presenting a potential therapeutic target for the treatment of docetaxel resistant BC.

Significance of TFF3 protein and Her-2/neu status in patients with gastric adenocarcinoma

Increased knowledge of molecular alterations involved in gastric carcinogenesis has provided useful information for diagnosis and prediction. In this study, we investigated the clinicopathological significance of TFF3 expression and Her-2/neu status in gastric adenocarcinoma and explored the correlation between TFF3 expression and Her-2/neu status. A hundred and twenty-six (126) patients having undergone curative gastrectomy were enrolled. Immunohistochemistry for TFF3 was performed on tumor tissues and non-neoplastic resection margins. Her-2/neu status was assessed by immunohistochemical staining and fluorescence in situ hybridization (FISH) on tumor tissues. As a result, TFF3 expression and Her-2/neu positivity were detected in 46.8% and 11.9% of the cases, respectively. Patients with negative TFF3 exhibited longer survival than the positive group (P=0.0142), while patients with positive Her-2/neu only showed a tendency toward longer overall survival (P>0.05). However, Her-2/neu was significantly associated with improved disease-free survival (P=0.0234). Multivariate analysis demonstrated Her-2/neu and TFF3 to be independent prognostic indicators of recurrence, and a significantly poor prognosis for expression of TFF3 in patients with Her-2/neu negative tumors. TFF3 is an independent indicator for overall survival in gastric cancer, while Her-2/neu, as a marker of long time survival prediction, seems to be limited.

Impact of NPM, TFF3 and TACC1 on the Prognosis of Patients with Primary Gastric Cancer

Background NPM, TFF3 and TACC1 are molecular markers that play important roles in cell differentiation. Herein, we investigated their prognostic impact in patients with primary gastric cancer (GC) and determined whether they could be used as markers of more aggressive gastric carcinomas by detecting the extent of expression in human gastric carcinoma samples. Methodology/Principal Findings Tumor tissue specimens from 142 GC patients were retrospectively retrieved and immunohistochemically evaluated. Correlations between NPM, TFF3 and TACC1 over-expression and clincopathologic parameters, and their prognostic values were investigated with χ2, Kaplan-Meier method, and Cox uni- and multivariate survival models. NPM, TFF3 and TACC1 expression was significantly higher in GC patients with poorly differentiated histologic type than that in patients with well differentiated histologic type. NPM expression was significantly higher in patients with hepatic metastasis or recurrence than that in patients without metastasis. TFF3 expression was significantly higher in patients with positive lymph node metastasis than that in patients with negative lymph node metastasis. Age, lymph node metastasis, and TFF3 and TACC1 over-expression were significantly correlated with low survival (P<0.05, P<0.05, P = 0.005 and P = 0.009, respectively). Multivariate analysis showed that lymph node metastasis and TFF3 and TACC1 over-expression were independent prognostic factors. Conclusions TFF3 and TACC1 over-expression in epithelial cells of surgically resected GC tissues was an independent predictor of short survival in GC patients. The prognosis was poorer in patients with positive expression of both TFF3 and TACC1 than that in patients with positive expression of TFF3 or TACC1 alone, or with negative expression of TFF3 and TACC1.

Association of Mixed Lineage Kinase Domain-Like Protein Expression With Prognosis in Patients With Colon Cancer.

Background: The mixed lineage kinase domain-like protein has recently been identified as a key downstream component of tumor necrosis factor–induced necroptosis, which is an important pathway of cancer cell death. The goal of the current study is to explore the expression of mixed lineage kinase domain-like protein in colon cancer tissues and evaluate the prognostic value in patients with colon cancer. Methods: We collected normal and cancer colon tissues from 135 patients diagnosed with colon cancer after radical operation during July 2007 to April 2009 at The Affiliated Hospital of Qingdao University. Immunohistochemistry analysis was scored using an established scoring system. Kaplan-Meier survival curves were generated for recurrence-free survival and overall survival for all patients and 2 subsets of patients. The relationship between mixed lineage kinase domain-like protein expression and prognosis parameter (recurrence-free survival, overall survival) was analyzed by univariate and multivariate Cox regression analyses. Results: The median age of all patients was 67 years and 56.3% were male. Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival (78.6 vs 81.2 months; P = .011) in all patients. In the subset of 79 patients who received adjuvant chemotherapy, low expression of mixed lineage kinase domain-like protein was associated with decreased recurrence-free survival (60.4 vs 72.8 months; P = .032) and decreased overall survival (66.3 vs 72.9 months; P = .005). Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival (74.9 vs 79.8 months; P = .006) and recurrence-free survival (69.6 vs 78.8 months; P = .005) among patients with Tumor Node Metastasis (TNM) stage II colon cancer. Conclusions: Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival in all patient-group with resected colon cancer. It is associated with decreased recurrence-free survival and overall survival in the subset of patients who receive adjuvant chemotherapy and patients who were TNM stage II. Mixed lineage kinase domain-like protein may provide important prognostic information in patients with colon cancer.

Computed tomography-guided iodine-125 interstitial implantation as an alternative treatment option for lung cancer.

PURPOSE The aim was to evaluate the safety, feasibility and efficacy of computed tomography (CT)-guided percutaneous interstitial brachytherapy using radioactive iodine-125 ( 125 I) seeds for the treatment of lung cancer. MATERIALS AND METHODS Included in this study were 45 male and 35 female patients aged 52-85 years (mean 72-year) who were diagnosed with lung cancer. Of the 80 cases of lung cancer, 38 were pathologically confirmed as squamous cell carcinoma, 29 as adenocarcinoma, 2 as small cell lung cancer, and 11 as metastatic lung cancer. Percutaneous interstitial implantation of radioactive 125 I seeds was performed under CT guidance. The treatment planning system was used to reconstruct three-dimensional images of the tumor to determine the quantity and distribution of 125 I seeds to be implanted. Under CT guidance, 125 I seeds were embedded into the tumor, with the matched peripheral dose set at 100-130 Gy. Follow-up CT scan was done in 2-month to explore the treatment efficacy. RESULTS The procedure was successful in all patients. No major procedure-associated death occurred. The duration of follow-up was 6-month. Complete response (CR) was seen in 38 cases (47.5%), partial response (PR) in 27 cases (33.75%), stable disease (SD) in 10 cases (12.5%), and progressive disease in 5 cases (6.25%), with a local control rate (CR + PR + SD) of 93.75%. The 2-, 4- and 6-month overall response rate (CR + PR) was 78%, 83% and 81%, respectively. CONCLUSION Implantation of CT-guided 125 I seeds is a safe and effective alternative option for the treatment of lung cancer.

A Randomised Controlled Phase II Trial of the Combination of XELOX with Thalidomide for the First-line Treatment of Metastatic Colorectal Cancer

Objective To evaluate the efficacy and safety of the combination of XELOX regimen (oxaliplatin plus capecitabine) with thalidomide for the first-line treatment of metastatic colorectal cancer (MCRC). Methods All of the 89 patients with MCRC who fulfilled eligibility criteria were randomly assigned to treatment group (n=44) and control group (n=45). The treatment group received a combination of XELOX with thalidomide and the control group received XELOX alone. Each patient received at least 2 cycles of treatment (1 cycle=21 d). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR) as well as disease control rate (DCR). Drug safety and quality of life were also assessed. Results The median PFS of the treatment and control groups were 5.6 and 5.2 months, respectively. The difference did not have a statistical significance (P=0.307). The ORRs of the two groups also had no statistical difference (34.1% vs. 26.7%, P=0.446). The addition of thalidomide to XELOX significantly improved the DCR (63.6% vs. 42.2%, P=0.043). Among 24 patients with hepatic metastasis in the treatment group, 2 patients satisfied the surgical criteria after treatment but none of 23 patients in the control group did. Grade 3 or 4 constipation in patients treated with thalidomide was significantly increased (20.5% vs. 4.4%, P=0.022) but didn’t result in treatment interruption. The rate of lethargy was increased but the difference between the two groups had no statistical significance (13.6% vs. 4.4%, P=0.130). The quality of life had no statistical difference between the two groups. Conclusions The combination of XELOX with thalidomide for the first-line treatment of MCRC was well tolerated. Statistically significant improvement was achieved for the DCR but not for PFS.

Overexpression of Her-2 upregulates FoxM1 in gastric cancer

The transcription factor, forkhead box protein M1 (FoxM1), and the tyrosine kinase receptor, human epidermal growth factor receptor-2 (Her-2), are aberrantly expressed in a number of human malignancies, and are closely associated with the development of cancer. However, their regulatory mechanisms and their involvement in tumor development have not been extensively investigated, particularly in gastric cancer. In the present study, we examined the expression levels of FoxM1 and Her-2 in samples from patients with gastric cancer, as well as gastric cancer cell lines. Their regulatory mechanisms and the connection between them were also explored. We found that FoxM1 and Her-2 expression was markedly higher in the gastric cancer samples, while a strong association was found between them at the mRNA and protein level. When we regulated the levels of Her-2 in the gastric cancer cell lines, the expression of FoxM1 changed accordingly. Following the transfection of Her-2 expression vectors into the gastric cell lines, the luciferase activity of the FoxM1 promoter positively increased along with the concentration of pcDNA3.1-Her-2. However, Her-2-siRNA inverted this variation, which was further confirmed by treatment with the Her-2 inhibitor, trastuzumab, revealing that Her-2 regulates FoxM1 expression at the promoter level in gastric cancer cells. Our results suggest that FoxM1 and Her-2 are important diagnostic markers for gastric cancer. FoxM1 may be a potential cellular target for therapeutic intervention, particularly in gastric cancers resistant to Her-2-targeted therapy.

Gemcitabine-based chemotherapy in colon squamous cell carcinoma: A case report and literature review

Squamous cell carcinoma (SCC) originating from the colon is rare. In terms of its clinicopathological characteristics, this type of cancer has been reported to be more aggressive and have a worse prognosis compared with adenocarcinoma. We herein present a successful therapeutic approach applying neoadjuvant and adjuvant gemcitabine-based chemotherapy in a patient with colon SCC. A 58-year-old male patient received two cycles of neoadjuvant chemotherapy with a regimen including gemcitabine, oxaliplatin and capecitabine, followed by radical excision and six cycles of adjuvant chemotherapy. Contrast-enhanced computed tomography and serum tumor markers were used for reassessment and evaluation was based on the World Health Organization criteria. Following neoadjuvant chemotherapy, the mass had shrunk and the patient was classed as having stable disease. Surgery and adjuvant chemotherapy were then performed and the patient had achieved a progression-free survival of 10 months when this report was submitted. Therefore, gemcitabine may be a treatment option for colon SCC in the neoadjuvant and/or adjuvant chemotherapy setting.