Deyun Luo

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.

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

OBJECTIVE To 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. METHODS Patients 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. RESULTS Between 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. CONCLUSION Adjuvant 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.

Prospective randomized phase II study of FOLFIRI versus FOLFOX7 in advanced gastric adenocarcinoma: a Chinese Western Cooperative Gastrointestinal Oncology Group Study

Until now, no standard chemotherapy has been widely accepted for advanced gastric cancer (GC). The current research aimed to compare folinic acid, fluorouracil with irinotecan (mFOLFIRI) or with oxaliplatin (mFOLFOX7) as first-line treatments in patients with locally advanced GC in an open, randomized, phase II study. Previously untreated metastatic or recurrent GC patients with measurable disease received mFOLFIRI (arm A) or mFOLFOX7 (arm B) every 2 weeks. The defined second-line treatment was mFOLFOX7 for arm A and mFOLFIRI for arm B. Primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), disease control rate (DCR) and toxicity. The evaluable population consisted of 128 patients (54 in arm A; 74 in arm B). Median PFS of arm A was 2.9 months (m) (95% confidence interval, CI, 1.9 to 4.1 m) versus 4.1 m (95% CI, 3.2 to 4.8 m) for arm B (p = 0.109). Median OS was 9.9 months (95% CI, 6.0 to 13.5 m) for arm A versus 12.0 m for arm B (95% CI, 10.3 to 13.7m; p = 0.431). DCRs for arm A and arm B were 59.3% and 66.3%, respectively (p = 0.850). In subgroup analysis of the patients who completed both treatment lines per protocol, the median first-line PFS was 2.1 m for the mFOLFIRI/mFOLFOX7arm versus 8.0 m for the mFOLFOX7/mFOLFIRI arm (p = 0.053), and the median second-line PFS values were 1.2 m versus 5.1 m (p = 0.287). Total PFS and OS were 8.1m and 11.0 m for the mFOLFIRI/mFOLFOX7 group compared with 12.2m and 20.2 m for the mFOLFOX7/mFOLFIRI group (p = 0.008, p = 0.030). Both regimens were well-tolerated with acceptable and manageable toxicities. Hence, there was no significant difference in the PFS or DCR. However, mFOLFOX7 followed by mFOLFIRI might have a better OS.Until now, no standard chemotherapy has been widely accepted for advanced gastric cancer (GC). The current research aimed to compare folinic acid, fluorouracil with irinotecan (mFOLFIRI) or with oxaliplatin (mFOLFOX7) as first-line treatments in patients with locally advanced GC in an open, randomized, phase II study. Previously untreated metastatic or recurrent GC patients with measurable disease received mFOLFIRI (arm A) or mFOLFOX7 (arm B) every 2 weeks. The defined second-line treatment was mFOLFOX7 for arm A and mFOLFIRI for arm B. Primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), disease control rate (DCR) and toxicity. The evaluable population consisted of 128 patients (54 in arm A; 74 in arm B). Median PFS of arm A was 2.9 months (m) (95% confidence interval, CI, 1.9 to 4.1 m) versus 4.1 m (95% CI, 3.2 to 4.8 m) for arm B (p = 0.109). Median OS was 9.9 months (95% CI, 6.0 to 13.5 m) for arm A versus 12.0 m for arm B (95% CI,10.3 to 13.7m; p = 0.431). DCRs for arm A and arm B were 59.3% and 66.3%, respectively ( p = 0.850). In subgroup analysis of the patients who completed both treatment lines per protocol, the median first-line PFS was 2.1 m for the mFOLFIRI/mFOLFOX7arm versus 8.0 m for the mFOLFOX7/mFOLFIRI arm (p = 0.053), and the median second-line PFS values were 1.2 m versus 5.1 m (p= 0.287). Total PFS and OS were 8.1m and 11.0 m for the mFOLFIRI/mFOLFOX7 group compared with 12.2m and 20.2 m for the mFOLFOX7/mFOLFIRI group (p= 0.008, p= 0.030). Both regimens were well-tolerated with acceptable and manageable toxicities. Hence, there was no significant difference in the PFS or DCR. However, mFOLFOX7 followed by mFOLFIRI might have a better OS.