Miao Feng

miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1

miR-320 expression level is found to be down-regulated in human colon cancer. To date, however, its underlying mechanisms in the chemo-resistance remain largely unknown. In this study, we demonstrated that ectopic expression of miR-320 led to inhibit HCT-116 cell proliferation, invasion and hypersensitivity to 5-Fu and Oxaliplatin. Also, knockdown of miR-320 reversed these effects in HT-29 cells. Furthermore, we identified an oncogene, FOXM1, as a direct target of miR-320. In addition, miR-320 could inactive the activity of Wnt/β-catenin pathway. Finally, we found that miR-320 and FOXM1 protein had a negative correlation in colon cancer tissues and adjacent normal tissues. These findings implied that miR-320-FOXM1 axis may overcome chemo-resistance of colon cancer cells and provide a new therapeutic target for the treatment of colon cancer.

A phase II study of modified FOLFOX as first-line chemotherapy in advanced small bowel adenocarcinoma.

This study aimed at assessing the efficacy and safety of biweekly oxaliplatin in combination with continuous infusional 5-fluorouracil and leucovorin (modified FOLFOX regimen) in patients with advanced small bowel adenocarcinoma (SBA). Thirty-three eligible patients with previously untreated SBA received 85 mg/m2 of oxaliplatin intravenously over a 2-h period on day 1, together with 400 mg/m2 of leucovorin over 2 h, followed by a 46-h infusion of 5-FU 2600 mg/m2 every 2 weeks. All patients were evaluable for efficacy and toxicity. A median of nine cycles (range 3–18) was administered. The objective response rate was 48.5% [95% confidence interval (95% CI): 31–67%], with one complete response, 15 partial responses, 12 stable diseases, and five progressions. The median time to progression was 7.8 months (95% CI: 6.0–9.6) and the median overall survival was 15.2 months (95% CI: 11.0–19.4). Toxicity was fairly mild. Grade 3 toxicities included neutropenia (12.1%), thrombocytopenia (3.0%), nausea (6.1%), vomiting (3.0%), diarrhea (3.0%), peripheral neuropathy (9.1%), and fatigue (3.0%), and grade 4 toxicities occurred in none of the patients. The modified FOLFOX regimen is highly active and well tolerated as first-line chemotherapy for advanced SBA patients.

MiR-1271 Inhibits Cell Proliferation, Invasion and EMT in Gastric Cancer by Targeting FOXQ1.

Background/Aims: FOXQ1 overexpression has been reported to enhance tumor growth and invasion. However, the biological function of FOXQ1 and the mechanism underlying its upregulation in gastric cancer (GC) remain unknown. Methods: QPCR was used to detect the expression of miR-1271 and FOXQ1 in specimens from GC patients. FOXQ1-siRNA, and miR-1271 mimics and inhibitor were transfected into human MGC-803 and SGC-7901 cells. The transwell assay was used to examine the cell invasive ability. The regulation mechanism was confirmed by luciferase reporter assay. Markers of epithelial-mesenchymal transition (EMT) were detected by western blot analysis. Results: MiR-1271 was downregulated in both GC tissues and GC cell lines. The expression of miR-1271 was inversely correlated with tumor size (P = 0.017), tumor stage (P = 0.035), lymph node metastasis (P = 0.018), and TNM stage (P = 0.025). Ectopic expression of miR-1271 dramatically suppressed GC cell proliferation, invasion, and EMT. Furthermore, FOXQ1 was identified as a direct target of miR-1271. Knockdown of FOXQ1 inhibited GC cell malignant behavior, whereas FOXQ1 overexpression partially restored the suppression effects of miR-1271. Additionally, miR-1271 expression was negatively correlated with FOXQ1 in GC tissues. Conclusions: MiR-1271 inhibits cell proliferation, invasion, and EMT in GC by directly suppressing FOXQ1 expression.

MicroRNA-506 inhibits gastric cancer proliferation and invasion by directly targeting Yap1

Increasing evidence indicates that microRNA (miR)-506 plays a vital role in tumorigenesis; however, the role of miR-506 in gastric cancer (GC) is unclear and needs further investigation. In the present study, we showed that the decrease in the expression of miR-506 is associated with tumor size, pathological tumor node metastasis (TNM) stage, and lymph node metastasis in 63 GC patient tumors. We found that patients with lower expression of miR-506 had a poor prognosis than that with the patients with high expression of miR-506. Notably, the ectopic expression of miR-506 was sufficient to inhibit cell proliferation, invasion, and epithelial-mesenchymal transition in the GC cells. Moreover, results from luciferase reporter assays identified miR-506 as a direct regulator of Yes-associated protein 1 (Yap1). Reintroduction of Yap1 rescues miR-506-induced effects on SGC-7901 cell proliferation and invasion. This function of miR-506/Yap1 axis is clinically significant, as the level of miR-506 is inversely correlated with Yap1 mRNA expression in matched tissues. Thus, our study demonstrates that miR-506 may act as a tumor suppressor in GC and that the miR-506/Yap1 axis may help us better understand the molecular mechanisms of GC progression.

A phase II study of modified FOLFOX as first-line chemotherapy in elderly patients with advanced gastric cancer

The aim of this study was to evaluate the efficacy and safety of biweekly oxaliplatin in combination with continuous infusional 5-fluorouracil and leucovorin (modified FOLFOX regimen) in elderly patients with advanced gastric cancer (AGC). Forty-six eligible patients older than 65 years with previously untreated AGC received oxaliplatin 85 mg/m2 intravenously over a 2-h period on day 1, together with leucovorin 400 mg/m2 over 2 h, followed by a 46-h infusion of 5-fluorouracil 2600 mg/m2 every 2 weeks. All patients were evaluable for efficacy and toxicity. A median of seven cycles (range 1–12) was administered. The overall response rate was 45.6% [95% confidence interval (CI): 31–61%] with two complete responses, 19 partial responses, 15 stable diseases, and 10 progressions. Median time to progression was 6.2 months (95% CI: 4.6–7.8) and median overall survival was 9.8 months (95% CI: 8.2–11.4). Toxicity was fairly mild. Grade 3 toxicities included neutropenia (8.7%), nausea (4.3%), vomiting (4.3%), diarrhea (2.2%); and grade 4 toxicities occurred in none of the patients. Grades 1–2 peripheral neuropathy was reported in 43.5% of patients. The modified FOLFOX regimen is active, well tolerated as first-line chemotherapy for elderly patients aged above 65 years with AGC.

Cullin 4A (CUL4A), a direct target of miR-9 and miR-137, promotes gastric cancer proliferation and invasion by regulating the Hippo signaling pathway

Although Cullin 4A (CUL4A) is mutated or amplified in several human cancer types, its role in gastric cancer (GC) and the mechanisms underlying its regulation remain largely uncharacterized. In the present study, we report that the expression of CUL4A significantly correlated with the clinical stage of the tumor and lymph node metastasis, and survival rates were lower in GC patients with higher levels of CUL4A than in patients with lower CUL4A levels. The upregulation of CUL4A promoted GC cell proliferation and epithelial-mesenchymal transition (EMT) by downregulating LATS1-Hippo-YAP signaling. Knocking down CUL4A had the opposite effect in vitro and in vivo. Interestingly, CUL4A expression was inhibited by the microRNAs (miRNAs), miR-9 and miR-137, which directly targeted the 3′-UTR of CUL4A. Overexpression of miR-9 and miR-137 downregulated the CUL4A-LATS1-Hippo signaling pathway and suppressed GC cell proliferation and invasion in vitro. Taken together, our findings demonstrate that perturbations to miR-9/137-CUL4A-Hippo signaling contribute to gastric tumorigenesis, and suggest potential therapeutic targets for the future treatment of GC.

Resveratrol Treatment Inhibits Proliferation of and Induces Apoptosis in Human Colon Cancer Cells

Background Resveratrol, a natural isolate from plant sources, has a long and important history in traditional Chinese medicine. In the present study we investigated the effect of resveratrol on human colon cancer cell lines. Material/Methods We used the Cell Counting kit-8 (CCK-8) for determination of colon cancer cell viability. Apoptosis induction was analyzed using the DeadEnd™ Colorimetric TUNEL System (Promega, Madison, WI, USA). The siRNA Transfection Reagent kit (Santa Cruz Biotechnology, Inc.) was used for the administration of COX-2 silencer RNA (siRNA) into the colon cancer cells. Primer Express® software for Real-Time PCR ver. 3.0 (Applied Biosystems, Foster City, CA, USA) was used to prepare the primers for RT-PCR. Results The results revealed that exposure of colon cancer cells to resveratrol inhibited cell viability. Resveratrol exhibited a significant inhibitory effect on cell viability at 30 μM concentration after 48 h of exposure. We observed that 30-μM doses of resveratrol for 72 h led to 18, 29, and 34% reduction in the viability of HCA-17, SW480, and HT29 cells, respectively. It also significantly induced apoptosis in both of the tested carcinoma cell lines. The population of apoptotic cells in HCA-17 and SW480 cell lines after 48 h of resveratrol treatment was 59.8±4 and 67.2±4%, respectively, compared to 2.3±1% in the control cells. The colon cancer cells exposed to resveratrol showed significantly lower cyclooxygenase-2 and prostaglandin receptor expression. Treatment of colon cancer cells with the inhibitor of cyclooxygenase-2, indomethacin, and administration of silencer RNA for cyclooxygenase-2 also produced similar results. Conclusions These findings suggest that resveratrol treatment can be a promising strategy for the treatment of colon cancer.

Interference with the β-catenin gene in gastric cancer induces changes to the miRNA expression profile

Aberrant activation of the Wnt/β-catenin signaling pathway plays a major role in carcinogenesis and the progression of many malignant tumors, especially gastric cancer (GC). Some research has suggested that expression of the β-catenin protein is associated with clinicopathologic factors and affects the biological behaviors of GC cells. However, the mechanism of these effects is not yet clear. Studies show that the Wnt/β-catenin pathway regulates some miRNAs. We hypothesize that oncogenic activation of β-catenin signaling is involved in the formation of GC through regulating certain microRNAs (miRNAs). The results of the current study demonstrate that expression of the β-catenin protein is associated with many clinicopathologic characteristics including the degree of differentiation, depth of tumor invasion, tumor site, and 5-year survival rate. We found that silencing the expression of β-catenin with lentiviruses could delay cell proliferation, promote apoptosis, weaken the invasive power of GC cells, and increase the sensitivity of GC cells to 5-fluorouracil in vitro. Using miRNA microarrays to detect changes in the miRNA transcriptome following interference with β-catenin in GC cells, we found that miR-1234-3p, miR-135b-5p, miR-210, and miR-4739 were commonly upregulated and that miR-20a-3p, miR-23b-5p, miR-335-3p, miR-423-5p, and miR-455-3p were commonly downregulated. These data provide a theoretical basis for the potential interaction between miRNA and the β-catenin signaling pathway in GC.

A Phase II Study of Capecitabine plus Oxaliplatin as First-Line Chemotherapy in Elderly Patients with Advanced Gastric Cancer

Objective: This study aimed at assessing the efficacy and safety of oxaliplatin plus oral capecitabine (XELOX regimen) as first-line chemotherapy in elderly patients with advanced gastric cancer (AGC). Patients and Methods: Forty-six eligible patients aged ≧70 years with previously untreated AGC received oxaliplatin 130 mg/m2 intravenously over a 2-hour period on day 1 plus oral capecitabine 850 mg/m2 twice daily on days 1–14, every 3 weeks. Results: All patients were evaluable for toxicity and 45 patients for efficacy. A median of 6 cycles (range 1–8) was administered. The overall response rate was 48.9% (95% CI 34–64) with 1 complete response, 21 partial responses, 15 stable diseases and 8 progressions. Median time to progression was 6.0 months (95% CI 3.9–8.1), and the median overall survival was 10.0 months (95% CI 8.6–11.4). Toxicity was fairly mild. Grade 3 toxicities included neutropenia (6.5%), thrombocytopenia (2.2%), nausea (2.2%), vomiting (4.3%), diarrhea (4.3%) as well as peripheral neuropathy (2.2%); grade 4 toxicities occurred in none of the patients. Conclusion: The XELOX regimen with capecitabine at a lower dose of 850 mg/m2 is active, fairly tolerable and conveniently delivered as first-line chemotherapy for elderly AGC patients.

A Phase II Trial of Epirubicin, Oxaliplatin, and Capecitabine (EOX) as First-Line Chemotherapy in Advanced Gastric Cancer: A Chinese Single-Center Experience

Objective: This study aimed at evaluating the efficacy and safety of epirubicin, oxaliplatin, and capecitabine (EOX) in advanced gastric cancer (AGC) patients in the Chinese population. Patients and Methods: Patients with previously untreated advanced measurable gastric cancer received epirubicin (50 mg/m2, day 1), oxaliplatin (130 mg/m2 2-hour infusion, day 1) and capecitabine (625 mg/m2 orally, twice daily, days 1–21) every 3 weeks.Results: Of 48 enrolled patients, 47 were evaluable for efficacy and 48 for toxicity. A median of five cycles (range 1–8) was administered. The overall response rate was 51.1% (95% CI 36–66) with two complete responses, 22 partial responses, 16 stable diseases, and 7 progressions. Median progression-free survival was 6.5 months (95% CI 5.6–7.4) and median overall survival was 10.4 months (95% CI 8.8–12.0). Grade 3–4 neutropenia and anemia were observed in 22.9 and 6.3% of patients, respectively. Grade 3–4 nonhematological toxicities included alopecia (18.9%), nausea (8.3%), vomiting (6.3%), diarrhea (6.3%), hand-foot syndrome (4.2%) and neurological toxicity (2.1%). Conclusion: In our experience, the EOX regimen was highly effective, well tolerated and conveniently delivered as first-line chemotherapy for AGC patients in the Chinese population.