Meng Qiu

miR-137 targets Cdc42 expression, induces cell cycle G1 arrest and inhibits invasion in colorectal cancer cells.

miRNAs have emerged as post‐transcriptional regulators that are critically involved in the pathogenesis of a number of human cancers. Cdc42, one of the best characterized members of the Rho GTPase family, is found to be up‐regulated in several types of human tumors and has been implicated in cancer initiation and progression. In the present study, we have identified miR‐137 as a potential regulator of Cdc42 expression. A bioinformatics search revealed a putative target‐site for miR‐137 within the Cdc42 3′ UTR at nt 792–798, which is highly conserved across different species. Expression of miR‐137 in colorectal cancer cell lines was found inversely correlated with Cdc42 expression. miR‐137 could significantly suppress Cdc42 3′ UTR luciferase‐reporter activity, and this effect was not detectable when the putative 3′ UTR target‐site was mutated. Consistent with the results of the reporter assay, ectopic expression of miR‐137 reduced both mRNA and protein expression levels of Cdc42 and mimicked the effect of Cdc42 knockdown in inhibiting proliferation, inducing G1 cell cycle arrest, and blocking invasion of the colorectal cancer cells, whereas anti‐miR‐137 expression led to the opposite effect. Furthermore, expression of miR‐137 suppressed the immediate downstream effector of Cdc42, PAK signaling. Our results suggest that miR‐137 may have a tumor suppressor function by directly targeting Cdc42 to inhibit the proliferation and invasion activities of colorectal cancer cells. They raise an interesting possibility that Cdc42 activity and function can be controlled by miRNAs in addition to the classic regulators such as guanine nucleotide exchange factors and GTPase‐activating proteins.

RhoA Regulates G1-S Progression of Gastric Cancer Cells by Modulation of Multiple INK4 Family Tumor Suppressors

RhoA, a member of the Rho GTPase family, has been extensively studied in the regulation of cytoskeletal dynamics, gene transcription, cell cycle progression, and cell transformation. Overexpression of RhoA is found in many malignancies and elevated RhoA activity is associated with proliferation phenotypes of cancer cells. We reported previously that RhoA was hyperactivated in gastric cancer tissues and suppression of RhoA activity could partially reverse the proliferation phenotype of gastric cancer cells, but the underlying mechanism has yet to be elucidated. It has been reported that RhoA activation is crucial for the cell cycle G1-S procession through the regulation of Cip/Kip family tumor suppressors in benign cell lines. In this study, we found that selective suppression of RhoA or its effectors mammalian Diaphanous 1 and Rho kinase (ROCK) by small interfering RNA and a pharmacologic inhibitor effectively inhibited proliferation and cell cycle G1-S transition in gastric cancer lines. Down-regulation of RhoA-mammalian Diaphanous 1 pathway, but not RhoA-ROCK pathway, caused an increase in the expression of p21Waf1/Cip1 and p27Kip1, which are coupled with reduced expression and activity of CDK2 and a cytoplasmic mislocalization of p27Kip1. Suppression of RhoA-ROCK pathway, on the other hand, resulted in an accumulation of p15INK4b, p16INK4a, p18INK4c, and p19INK4d, leading to reduced expression and activities of CDK4 and CDK6. Thus, RhoA may use two distinct effector pathways in regulating the G1-S progression of gastric cancer cells.(Mol Cancer Res 2009;7(4):570–80)

A distinct role of RhoB in gastric cancer suppression.

Although Rho family GTPases RhoA, RhoB and RhoC share more than 85% amino acid sequence identity, they may play distinct roles in tumor progression. RhoA and RhoC have been suggested to have positive effects on tumor progression, but the role of RhoB in cancer, particularly in gastric cancer, remains unclear. In our study, we have examined the expression levels of these three Rho GTPases in a large panel of specimens from gastric cancer patients by immunohistochemistry. We found that RhoA and RhoC expression were significantly elevated, while RhoB was reduced or absent, in surgically removed gastric cancer tissues when compared to normal gastric tissues. The significant reduction of RhoB expression was confirmed in another group of gastric cancer samples in comparison to the adjacent non‐neoplastic tissues. Then we transfected the plasmids containing RhoA, RhoB or RhoC cDNA into two gastric cancer cell lines, SGC7901 and AGS cells, respectively. By overexpression experiments, we found that RhoA promoted the gastric cancer cell proliferation and RhoC stimulated migration and invasion of the cancer cell. RhoB expression, however, significantly inhibited the proliferation, migration and invasion of the gastric cancer cells and also enhanced the chemosensitivity of these cells to anticancer drugs. It appears that RhoB plays an opposing role from that of RhoA and/or RhoC in gastric cancer cells. Our work suggests that RhoB may play a tumor suppressor role and subsequently may have potential implications in future targeted therapy.

Effect of BRAF V600E mutation on tumor response of anti-EGFR monoclonal antibodies for first-line metastatic colorectal cancer treatment: a meta-analysis of randomized studies

Anti-EGFR monoclonal antibodies (anti-EGFR MoAbs) in metastatic colorectal cancer (mCRC) treatment are still not effective in all patients. This study aimed to evaluate the relationship between BRAF V600E mutation and the tumor response of anti-EGFR MoAbs for first-line treatment in mCRC patients. We searched the MEDLINE and EMBASE databases, using the key words that included colorectal cancer, cetuximab, panitumumab, and BRAF mutation and retrieved 445 articles. Among them four were included in the systematic review. Relative risks (RRs) with 95xa0% confidence intervals (CI) for response rate were calculated. BRAF mutation carriers had worse ORR than non-carriers in mCRC patients with KRAS wild-type in first-line treatment whether adding anti-EGFR MoAb to chemotherapy or not (RRxa0=xa00.43, [95xa0% CI 0.16–0.75]; RRxa0=xa00.38, [95xa0% CI 0.20–0.73]). But in the unselected patients whose KRAS mutation were unknown, BRAF mutation carriers had similar ORR whether adding cetuximab to chemotherapy or not (RRxa0=xa00.45, [95xa0% CI 0.18–1.09]; RRxa0=xa00.57, [95xa0% CI 0.15–2.23]). In BRAF mutation carriers adding anti-EGFR MoAb to chemotherapy was similar to chemotherapy alone whether in patients with wild-type KRAS or unselected patients (RRxa0=xa01.61, [95xa0% CI 0.57–4.47]; RRxa0=xa00.71, [95xa0% CI 0.18–2.77]). But in the BRAF mutation non-carriers, adding anti-EGFR MoAb produced a clear benefit in response rate than chemotherapy alone and this advantage was restricted to KRAS wild-type patients (RRxa0=xa01.48, [95xa0% CI 1.28–1.71]). BRAF mutation decreases tumor response in first-line treatment whether cetuximab was given or not in patients with KRAS wild-type, and anti-EGFR MoAb produces a clear benefit in response rate in patients with BRAF and KRAS wild-type.

Synergistic antitumor effect of TRAIL and adriamycin on the human breast cancer cell line MCF-7

The aim of the present study was to determine the effect of the combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and adriamycin (ADM) on the human breast cancer cell line MCF-7 and to identify potential mechanisms of apoptosis. Cell viability was analyzed by the MTT assay and the synergistic effect was assessed by the Webb coefficient. Apoptosis was quantified using the annexin V-FITC and propidium iodide staining flow cytometry. The mRNA expression of TRAIL receptors was measured by RT-PCR. Changes in the quantities of Bax and caspase-9 proteins were determined by Western blot. MCF-7 cells were relatively resistant to TRAIL (IC50 >10 microg/mL), while MCF-7 cells were sensitive to ADM (IC50 <10 microg/mL). A subtoxic concentration of ADM (0.5 microg/mL) combined with 0.1, 1, or 10 microg/mL TRAIL had a synergistic cytotoxic effect on MCF-7 cells, which was more marked with the combination of TRAIL (0.1 microg/mL) and ADM (0.5 microg/mL). In addition, the combined treatment with TRAIL and ADM significantly increased cell apoptosis from 9.8% (TRAIL) or 17% (ADM) to 38.7%, resulting in a synergistic apoptotic effect, which is proposed to be mediated by up-regulation of DR4 and DR5 mRNA expression and increased expression of Bax and caspase-9 proteins. These results suggest that the combination of TRAIL and ADM might be a promising therapy for breast cancer.

Antiemetic activity of megestrol acetate in patients receiving chemotherapy

PurposeSeveral trials had independently noted that patients receiving megestrol acetate had less nausea and vomiting, but this antiemetic activity of megestrol acetate has not been reported separately in the literature. Our objective was to evaluate the antiemetic ability of megestrol acetate in patients receiving chemotherapy.Patients and MethodsPatients receiving chemotherapy were randomly assigned to receive either megestrol acetate 320xa0mg PO or placebo before the first day of chemotherapy, followed on days 1–4 by megestrol acetate 320xa0mg PO combined with granisetron 3xa0mg IV and metoclopramide 20xa0mg IM or only granisetron 3xa0mg IV combined with metoclopramide 20xa0mg IM in a crossover manner during two consecutive cycles. Rates of complete protection against both vomiting and moderate-to-severe nausea was the primary end point.ResultsOne hundred patients were enrolled in the study. The antiemetic regimen containing megestrol acetate was superior in providing complete protection from nausea and vomiting (45% megestrol acetate regimen vs.17% no megestrol acetate regimen). Complete response of acute phase in both antiemetic regimens was different (85% megestrol acetate regimen vs. 72% no megestrol acetate regimen). Complete response of delayed emesis was also different (49% megestrol acetate regimen vs. 18% no megestrol acetate regimen). Adverse events were mostly mild to moderate. There were no serious drug-related adverse events between the two antiemetic regimens.ConclusionMegestrol acetate was shown to be an effective antiemetic agent. Megestrol acetate might be a new antiemetic option for chemotherapy.

Surgical management for non-functional pancreatic neuroendocrine neoplasms with synchronous liver metastasis: A consensus from the Chinese Study Group for Neuroendocrine Tumors (CSNET)

Pancreatic neuroendocrine neoplasms (p-NENs) are slowly growing tumors with frequent liver metastasis. There is a variety of approaches to treat non-functional p-NENs with synchronous liver metastasis (LM) which complicates the determination of optimal treatment. Based on updated literature review, we discussed the treatment strategy determinants for p-NEN with LM. According to the resectability of primary tumor, the WHO 2010 grade classification and the radiological type of liver metastasis, the CSNET group reached agreements on a number of issues, including the following. Prior to treatment, biopsy is required to confirm pathology. Liver biopsy is important for more accurate grading of tumor and percutaneous core needle biopsy is more available than EUS-FNA. In patients with unresectable primary, surgical resection for liver-metastatic lesions should be avoided. Curative surgery is recommended for G1/G2 p-NET with type I LM and R1 resection also seems to improve overall survival rate. Cytoreductive surgery is recommended for G1/G2 p-NET with type II LM in select patients, and should meet stated requirements. Surgical resection for G1/G2 p-NET with type III LM and p-NEC with LM should be avoided, and insufficient evidence exists to guide the surgical treatment of G3 p-NET with LM. Liver transplantation may be an option in highly select patients. In addition, the optimal time for surgical approach is still required for more evidence.

Postoperative chemoradiotherapy in gastric cancer: a phase I study of radiotherapy with dose escalation of oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX regimen)

Concurrent chemoradiotherapy begins to be more and more widely accepted as a standard adjuvant treatment in gastric cancer. And oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) also reveals to be a very effective regimen in gastric cancer. But the safety and the dosages of FOLFOX combining with radiotherapy are still unknown. This study was to determine the maximum-tolerated dose and the dose-limiting toxicity of FOLFOX with higher-dose concurrent radiotherapy (RT) as adjuvant treatment in patients with gastric cancer. Patients with Stage II/III gastric cancer after surgery were recruited. They received one cycle of induction chemotherapy (standard FOLFOX4). Then, they received 50.4xa0Gy in 1.8-Gy fractions in combination with two cycles of concurrent FOLFOX, and oxaliplatin among this regimen was administered with escalating doses. Dose-limiting toxicity including grade 3 or grade 4 hematologic and nonhematologic toxicities was investigated. Fifteen patients were enrolled at the following dose levels: oxaliplatin 55xa0mg/m2 (3 patients), 65xa0mg/m2 (6 patients), and 75xa0mg/m2 (6 patients). Dose-limiting toxicity was observed in 1 patient at 65xa0mg/m2 (grade 4 leukopenia) and in 3 patients at 75xa0mg/m2 (1 patient had grade 4 leukopenia, 1 had grade 3 thrombocytopenia, and 1 had grade 3 stomatitis). Combination chemotherapy FOLFOX with oxaliplatin 65xa0mg/m2, dxa01; leucovorin 200xa0mg/m2, 2xa0h, d1–2; 5-fluorouracil 400xa0mg/m2, iv, dxa01–2 and 600xa0mg/m2 civ, 22xa0h, dxa01–2 given concurrently with RT (50.4xa0Gy) can be recommended as a safer and preferable regimen for the adjuvant treatment of patients with gastric cancer.

Adjuvant intensity-modulated radiotherapy (IMRT) with concurrent paclitaxel and cisplatin in cervical cancer patients with high risk factors: A phase II trial

OBJECTIVEnTo evaluate the safety and efficacy of adjuvant intensity-modulated radiotherapy (IMRT) with concurrent paclitaxel and cisplatin (TP) in early stage cervical cancer patients with high risk factors after radical hysterectomy.nnnMETHODSnPatients who underwent radical hysterectomy for FIGO stage IB-IIA cervical cancer and had high risk factors for recurrence were recruited. One cycle of TP was delivered before and after concurrent chemoradiotherapy, respectively. Concurrent chemoradiotherapy began 21 days after the start of the initial cycle of the chemotherapy with two cycles of TP delivered on day 1 and day 29 of radiotherapy. Primary endpoints were overall survival (OS) and relapse-free survival (RFS), with toxicities, local-regional control (LC) and distant failure (DF) rate as secondary endpoints.nnnRESULTSnBetween 2008 and 2012, 67 patients were evaluable. The 2 and 4-year RFS rates were 98.2% and 92.9%. Corresponding OS rates were 100%, and 98.0%, respectively. The 4-year LC and DF rates were 98.0% and 5.2%, respectively. Grade 3-4 acute leucopenia, neutropenia and thrombocytopenia occurred in 25.4%, 11.9% and 1.5% of patients, respectively. There were 89.6% and 59.7% patients experienced acute vomiting and diarrhea, but only 6.0% and 6.0% patients were grade 3, respectively. No case of chronic toxicity exceeded grade 2.nnnCONCLUSIONnAdjuvant concurrent IMRT with paclitaxel plus cisplatin are safe and effective in early stage cervical cancer patients with high risk factors for recurrence following radical hysterectomy.

The Rho GTPase RhoE is a p53-regulated candidate tumor suppressor in cancer cells

Previous studies have shown that RhoE, an atypical member of the Rho GTPase family, may play an opposite role to RhoA in regulating cell proliferation and invasion. To explore the relationship between RhoE and the malignant phenotypes of human cancer, we have determined the expression patterns of RhoE in varying grade of human cancer tissues and tested the effects of RhoE expression in several RhoE underexpressing cancer cell lines. Systemic immunocytochemistry analyses of gastric, colorectal, lung and breast carcinomas, respectively, showed that RhoE protein expression was significantly decreased in most cancer cases compared with that of adjacent normal tissues. Enhanced RhoE expression could markedly inhibit proliferation, migration and invasion and induce apoptosis of the cancer cells which have relatively low levels of endogenous RhoE expression. Wild-type p53 (wt-p53) could strongly increase RhoE expression in p53-transfected cells. Furthermore, the luciferase assays indicated that wt-p53 significantly enhanced the activities of RhoE promoter compared with mutant p53 (mt-p53) in PC3 cells (p53 null). Collectively, data are presented showing that RhoE may participate in human cancer progression and act as a candidate target of p53, and these findings also strongly suggest that RhoE may be a new candidate tumor suppressor and could serve as a potential target in the gene therapy of cancer.