Xiangdong Cheng

Knockdown of Long Non-coding RNA HOTAIR Suppresses Tumor Invasion and Reverses Epithelial-mesenchymal Transition in Gastric Cancer

Background: Over-expression of long non-coding RNA HOTAIR has been reported in several types of cancer. Yet its involvement in gastric cancer (GC) has not been well understood. The aim of present study was to examine the expression pattern of HOTAIR in GC patients, then, explore its role in promoting cancer invasion and underlying molecular mechanism. Methods: The expression level of HOTAIR in the tumor specimens of GC patients was quantified by Realtime RT-PCR. The correlation between HOTAIR level and clinicopathological factors as well as prognosis was then examined. Down-regulation of HOTAIR by RNA interference was applied to investigate its roles in tumor invasiveness via the view of Epithelial-to-mesenchymal transition (EMT). Results: The expression level of HOTAIR in cancer tissues was higher than that in adjacent noncancerous tissues. Expression level of HOTAIR was significantly correlated with lymph node metastasis and TNM stage. Furthermore, high expression level of HOTAIR was a predictor of poor over-all survival in GC patients. In vitro, inhibition of HOTAIR in GC cells could reduce invasiveness, as well as the expression of MMP1 and MMP3. In addition, suppression of HOTAIR could reverse EMT process. Conclusions: HOTAIR could act as a potential predictor for over-all survival in patients with GC. Inhibition of HOTAIR could reduce invasiveness and reverse EMT process in GC cells, indicating the potential role of HOTAIR in GC diagnostics and therapeutics.

5-Fluorouracil chemotherapy of gastric cancer generates residual cells with properties of cancer stem cells.

Background: 5-Fluorouracil (5Fu) chemotherapy is the first treatment of choice for advanced gastric cancer (GC), but its effectiveness is limited by drug resistance. Emerging evidence suggests that the existence of cancer stem cells (CSCs) contributes to chemoresistance. The aim of the present study was to determine whether 5Fu chemotherapy generates residual cells with CSC-like properties in GC. Methods: Human GC cell lines, SGC7901 and AGS, were exposed to increasing 5Fu concentrations. The residual cells were assessed for both chemosensitivity and CSC-like properties. B lymphoma Mo-MLV insertion region 1 (BMI1), a putative CSC protein, was analyzed by immunohistochemical staining and subjected to pairwise comparison in GC tissues treated with or without neoadjuvant 5Fu-based chemotherapy. The correlation between BMI1 expression and recurrence-free survival in GC patients who received 5Fu-based neoadjuvant chemotherapy was then examined. Results: The residual cells exhibited 5Fu chemoresistance. These 5Fu-resistant cells displayed some CSC features, such as a high percentage of quiescent cells, increased self-renewal ability and tumorigenicity. The 5Fu-resistant cells were also enriched with cells expressing cluster of differentiation (CD)133+, CD326+ and CD44+CD24-. Moreover, the BMI1 gene was overexpressed in 5Fu-resistant cells, and BMI1 knockdown effectively reversed chemoresistance. The BMI1 protein was highly expressed consistently in the remaining GC tissues after 5Fu-based neoadjuvant chemotherapy, and BMI1 levels were correlated positively with recurrence-free survival in GC patients who received 5Fu-based neoadjuvant chemotherapy. Conclusions: Our data provided molecular evidence illustrating that 5Fu chemotherapy in GC resulted in acquisition of CSC-like properties. Moreover, enhanced BMI1 expression contributed to 5Fu resistance and may serve as a potential therapeutic target to reverse chemoresistance in GC patients.

TAK-242 can be the potential agents for preventing invasion and metastasis of hepatocellular carcinoma

The long-term prognosis of hepatocellular carcinoma (HCC) remains unsatisfactory even after surgical resection and chemoembolization because of a high recurrence rate. However, fewer agents are currently available to block or postpone HCC progression. Recent studies show that the activation of toll-like receptor 4 (TLR4)-NF-kappaB(NF-κB) signaling pathway can lead to the expression of interleukin (IL)-1, IL-6, IL-10, nitric oxide (NO) and tumor necrosis factor (TNF)-α, and promote chronic liver inflammation and malignant tumor development. A new small molecule TAK-242 (Resatorevid) can selectively inhibit TLR4-mediated signaling pathway and suppress the expression of inflammatory mediators. But the researches have not been reported whether TAK-242 can inhibit liver tumor growth and invasion. So it suggested a new hypothesis that TAK-242 selectively blocks the TLR4-NF-κB pathway and is hoped to be a potential and creative drug for preventing invasion and metastasis of HCC.

A modified pancreaticojejunostomy: kissing pancreaticojejunostomy.

Pancreaticoduodenectomy (Whipple procedure) has been the standard treatment for periampullary and pancreatic carcinoma. A leakage or fistula from the pancreatic anastomosis is the leading cause of morbidity and mortality after pancreaticoduodenectomy. In order to prevent the development of pancreatic fistula, we designed a modified pancreaticojejunostomy called Kissing Pancreaticojejunostomy, by which the pancreatic tube was tightly in touch with (kissing) the jejunal mucosa via a tent tube. We have performed this procedure on 71 consecutive patients and only one patient developed pancreatic fistula. It is a safe, simple and efficient technique.

Significance of MDR-related proteins in the postoperative individualized chemotherapy of gastric cancer

OBJECTIVES Post-operative adjuvant chemotherapy was beneficial for some patients; however, it may increase the treatment burden and reduce the immunity of other patients. Screening appropriate patients based on molecular markers for individualized adjuvant chemotherapy was necessary. MATERIALS AND METHODS Between June 2002 and June 2004, 119 patients who underwent radical gastrectomy were retrospectively analyzed. Some patients had adjuvant chemotherapy based on platinum and 5-FU for four to six cycles. Topoisomerase II (ToPo II) negative, multidrug resistance protein (MRP) positive, and glutathione S-transferase π (GST-π) positive were regarded as three risk factors that may be associated with chemotherapy resistance and poor prognosis. Patients were divided into two groups: high-risk group (≥ 2 risk factors) and the low-risk group (<2 risk factors), and the tumor recurrence and patient survival time of the two groups were analyzed. RESULTS The average recurrence time of the low-risk group was significantly longer than that of the high-risk group (21.29 ± 11.10 versus 15.16 ± 8.05 months, P < 0.01).The 3-year and 5-year survival rate of the high-risk group was 57.4% and 42.6%; however, it had no significant difference compared to 66.2% and 58.5% of the low-risk group (P > 0.05). In the high-risk group, the 3-year survival rate of patients with/without chemotherapy were 62.1% and 52.0%, 5-year survival rates were 44.8% and 40.0%, respectively, but the difference was not statistically significant (P > 0.05). In the low-risk group, the 3-year survival rate of patients with/without chemotherapy were 81.2% and 51.5%, and the 5-year survival rates were 71.9% and 45.5%, respectively, and the differences were statistically significant (P < 0.05). CONCLUSIONS Multidrug resistance (MDR)-related proteins ToPo II, MRP, and GST-ð had great significance for the individualized post-operative chemotherapy and prognosis of gastric cancer.

Aqueous Huaier Extract Suppresses Gastric Cancer Metastasis and Epithelial to Mesenchymal Transition by Targeting Twist

Trametes robiniophila Murr. (Huaier) is a widely used anti-cancer agent in China. Strong evidence for the anti-proliferative activity of Huaier has been reported; however, its anti-metastatic potential against gastric cancer (GC) as well as its underlying mechanism of action are unknown. Here, we show that treatment with an aqueous Huaier extract over a range of concentrations significantly suppressed both the invasiveness and migratory ability of GC cells. Huaier could also partly reverse the epithelial-mesenchymal transition (EMT), as characterized by increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers N-cadherin and vimentin. In addition, Huaier-treated cells expressed lower levels of Twist compared to untreated controls, and overexpression of Twist via transfection could partially abolish the anti-metastatic activity of Huaier. Furthermore, elevated Twist expression was correlated with an advanced TNM stage, a high rate of lymph node metastasis, and reduced disease-free survival in GC patients. These findings reveal a novel anti-metastatic mechanism for Huaier, which inhibits the EMT by targeting Twist, suggesting its potential application against a GC relapse.

D2 plus radical resection combined with perioperative chemotherapy for advanced gastric cancer with pyloric obstruction

A patient with advanced gastric cancer complicated with pyloric obstruction was treated using D2 + radical resection combined with perioperative chemotherapy, and had satisfying outcomes. The perioperative chemotherapy regimen was Taxol and S1 (tegafur, gimeracil, and oteracil). Three cycles of neoadjuvant chemotherapy were delivered before surgery, and three cycles of adjuvant therapy after surgery. PR was achieved after chemotherapy. D2 + dissection of stations 8p, 12b, 12p, 13 and 14v lymph nodes was performed on September 10, 2012.

Novel abdominal approach for dissection of advanced type II/III adenocarcinoma of the esophagogastric junction: a new surgical option

Objective The optimal surgical approach for Siewert type II adenocarcinoma of the esophagogastric junction (AEG) is controversial. In this study, we evaluated the outcomes of total gastrectomy for Siewert type II/III AEG via the left thoracic surgical approach that is used at our center. Methods We identified 41 patients with advanced AEG in our retrospective database and analyzed their 3-year survival rate, upper surgical margin, postoperative complications, and index of estimated benefit from lymph node dissection. Results The 3-year overall survival rate of the whole group was 63%, but no difference was observed between Siewert type II and III AEGs. Esophageal exposure and lymphadenectomy were sufficient. Eight patients developed postoperative complications, but none of the patients developed anastomotic leakage. Dissection of lymph node station Nos. 19 and 110 may be necessary for patients with Siewert type II AEG. Multivariate analysis revealed that the cT category was the only independent risk factor. Conclusions Total gastrectomy via an approach from the abdominal cavity into the thoracic cavity may be an optimal surgical technique for advanced Siewert type II AEG.