Expression of COX-2 and HER-2 in colorectal cancer and their correlation

AIM: To detect the expression of COX-2 and HER-2 in colorectal cancer and to analyze their correlation and clinical significance.METHODS: A total of 1026 colorectal cancer surgical specimens were collected from patients treated fromDecember 2002 to December 2007 at the First Affiliated Hospital of Anhui Medical University. All specimens were made into 4-μm slices. The expression of COX-2 and HER-2 were detected by immunohistochemistry using the streptavidin-biotin-peroxidase method. The correlations between COX-2 and HER-2 expression and colorectal cancer clinical features were analyzed.RESULTS: The positive rates of COX-2 and HER-2 expression in colorectal cancer were 77.97%(800/1026) and 46.20%(474/1026), respectively. There was a significant correlation between COX-2 and HER-2 expression in colorectal cancer(P < 0.05). In patients with tumor size ≥ 5 cm, the positive rates of COX-2 and HER-2 expression were 81.48%(308/378) and 57.94%(219/378), respectively. In patients with serosal invasion, the positive COX-2 and HER-2 expression rates were 80.53%(612/760) and 49.21%(374/760), respectively. In patients with lymph node metastasis, the positive expression rates were 85.04%(506/595) and 54.62%(325/595), respectively, and the positive expression rates differed significantly between patients with lymph node metastasis and those without(P < 0.05). In patients with Duke's C and D colorectal cancer, the positive COX-2 and HER-2 expression rates were 82.80%(443/535) and 57.94%(310/535), respectively. In patients with poorly differentiated colorectal cancer, the positive expression rates were 74.49%(210/282) and 52.84%(149/282), respectively(P < 0.05). In patients with distant metastasis, the positive expression rates were 82.27%(116/141) and 53.90%(76/141), respectively(P < 0.05). These findings suggest that COX-2 and HER-2 have synergistic effects in colorectal cancer. COX-2 and HER-2 expression had no significant correlation with sex, age, or tumor location. CONCLUSION: COX-2 and HER-2 are important markers for invasion and metastasis of colorectal cancer, and they act together to regulate the invasion and metastasis of colorectal cancer.

Antiproliferation and apoptosis induction of paeonol in HepG_2 cells

AIM: To investigate the antiproliferative effect of paeonol (Pae) used alone or in combination with chemotherapeutic agents [cisplatin (CDDP), doxorubicin (DOX) and 5-fluorouracil (5-FU)] on human hepatoma cell line HepG2 and the possible mechanisms. METHODS: The cytotoxic effect of drugs on HepG2 cells was measured by 3-(4, 5-dimethylthiazol-2- yl)-2, 5-diphenyltetra-zolium bromide (MTT) assay. Morphologic changes were observed by acridine orange (AO) fluorescence staining. Cell cycle and apoptosis rate were detected by flow cytometry (FCM). Drug-drug interactions were analyzed by the coefficient of drug interaction (CDI). RESULTS: Pae (7.81-250 mg/L) had an inhibitory effect on the proliferation of HepG2 cells in a dose-dependent manner, with the IC50 value of (104.77 ± 7.28) mg/L. AO fluorescence staining and FCM assays showed that Pae induced apoptosis and arrested cell cycle at S phase in HepG2 cells. Further, different extent synergisms were observed when Pae (15.63, 31.25, 62.5 mg/L) was combined with CDDP (0.31-2.5 mg/L), DOX (0.16-1.25 mg/L), or 5-FU (12.5-100 mg/L) at appropriate concentrations. The IC50 value of the three drugs decreased dramatically when combined with Pae (P < 0.01). Of the three different combinations, the sensitivity of cells to drugs was considerably different.CONCLUSION: Pae had a significant growth-inhibitory effect on the human hepatoma cell line HepG2, which may be related to apoptosis induction and cell cycle arrest. It also can enhance the cytotoxicity of chemotherapeutic agents on HepG2 cells, and the S phase arrest induced by Pae may be one of the mechanisms of these interactions.

Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation

AIM To clarify the mechanisms involved in the critical endoplasmic reticulum(ER) stress initiating unfolded protein response pathway modified by melatonin.METHODS Hepatoma cells, Hep G2, were cultured in vitro. Flow cytometry and TUNEL assay were used to measure Hep G2 cell apoptosis. Western blotting and quantitative reverse transcription-polymerase chain reaction methods were used to determine the protein and messenger RNA levels of ER stress and apoptosis related genes' expression, respectively. Tissue microarray construction from patients was verified by immunohistochemical analysis.RESULTS In the present study, we first identified that melatoninselectively blocked activating transcription factor 6(ATF-6) and then inhibited cyclooxygenase-2 (COX-2) expression, leading to enhanced liver cancer cell apoptosis under ER stress condition. Dramatically increased CCAAT-enhancer-binding protein homologous protein level, suppressed COX-2 and decreased Bcl-2/Bax ratio by melatonin or ATF-6 si RNA contributed the enhanced Hep G2 cell apoptosis under tunicamycin (an ER stress inducer) stimulation. In clinical hepatocellular carcinoma patients, the close relationship between ATF-6 and COX-2 was further confirmed.CONCLUSION These findings indicate that melatonin as a novel selective ATF-6 inhibitor can sensitize human hepatoma cells to ER stress inducing apoptosis.

Application of Paclitaxel-loaded EGFR Peptide-conjugated Magnetic Polymeric Liposomes for Liver Cancer Therapy

Developing the methodologies that allow for safe and effective delivery of therapeutic drugs to target sites is a very important research area in cancer therapy.In this study,polyethylene glycol(PEG)-coated magnetic polymeric liposome(MPL)nanoparticles(NPs)assembled from octadecyl quatemized carboxymethyl chitosan(OQC),PEGylated OQC,cholesterol,and magnetic NPs,and functionalized with epithelial growth factor receptor(EGFR)peptide,were successfully prepared for in-vivo liver targeting.The two-step liver targeting strategy,based on both magnetic force and EGFR peptide conjugation,was evaluated in a subcutaneous hepatocellular carcinoma model of nude mouse.The results showed that EGFR-conjugated MPLs not only accumulated in the liver by magnetic force,but could also diffuse into tumor cells as a result of EGFR targeting.In addition,paclitaxel(PTX)was incorporated into small EGFR-conjugated MPLs(102.0土0.7 nm),resulting in spherical particles with high drug encapsulation efficiency(>90%).The use of the magnetic targeting for enhancing the transport of PTX-loaded EGFR-conjugated MPLs to the tumor site was further confirmed by detecting PTX levels.In conclusion,PTX-loaded EGFR-conjugated MPLs could potentially be used as an effective drug delivery system for targeted liver cancer therapy.

颅骨测量数据揭示欧亚大陆东部史前人群扩散的"二层"模式

本文是基于考古发掘获取的人骨遗存在内的89组古代及现代的人群样本而做的颅骨形态测量研究,侧重说明解剖学意义上的现代人(anatomically modern humans)在欧亚大陆东部演化分布的“二层”模式。距今6.5万~5万年以前,“第一层”现代人经东南亚大陆向东、向南扩散,他们与现今安达曼人、澳大利亚人、巴布亚人的祖先以及日本绳纹时代人群最为接近。距今约九千年前,拥有东北亚血统的“第二层”现代人出现在中国中部地区,并于距今四千年前后向南扩张至东南亚地区,这些人群在颅骨形态上与西伯利亚人具有密切的亲缘关系。上述两大人群最初交流有限,在农业能够支撑增加人口密度的情境下,“第二层”现代人增长速度较快,人口数量较多。这两层人群显著的二重结构特征,表明了现代人在欧亚大陆南、北不同迁移路线间的历时性差异。