ABSTRACT
A palladium-catalyzed carbonylative Sonogashira/annulation reaction for the synthesis of indolo[1,2-b]isoquinolines has been developed. Tetracyclic 6/5/6/6 indoline skeletons were synthesized in moderate to good yields from easily available 2-bromo-N-(2-iodophenyl)benzamides and terminal alkynes. Notably, this efficient methodology established three C-C bonds and a C-N bond through a one-step transformation and provided a new method for the synthesis of indolo[1,2-b]isoquinoline derivatives.
ABSTRACT
Metastatic hepatocellular carcinoma (HCC) remains a mostly incurable disease. The fact that the identity of the mechanisms that regulate metastasis in HCC is known hampers the development of anti-metastatic therapies. Currently, there is no effective treatment for HCC once it is progressed to metastatic stage. Therefore, further study to elucidate the molecular mechanism underlying the metastasis of HCC is urgently required for the improvement of HCC treatment. Here, we describes actin gamma smooth muscle 2 (ACTG2) over-express in HCC and demonstrates high-expression of ACTG2 as a promising therapeutic target in HCC metastasis. The use of shRNA to knock-down ACTG2 impaired cells migration and invasion in vitro. Moreover, silencing of ACTG2 causes almost complete inhibition of metastasis in vivo. In contrast, overexpression ACTG2 significantly enforces HCC cells migration and metastasis. Finally, ACTG2 boosts the metastatic potential of HCC cells in a Notch homolog 1 (Notch1) dependent manner. Collectively, our study reveals a critical role of ACTG2 in HCC tumor metastasis, and renders it a novel target for the treatment of HCC.
Subject(s)
Actins/genetics , Carcinoma, Hepatocellular/genetics , Gene Expression Regulation, Neoplastic , Liver Neoplasms/genetics , Lung Neoplasms/genetics , Receptor, Notch1/genetics , Actins/antagonists & inhibitors , Actins/metabolism , Animals , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/therapy , Cell Line, Tumor , Cell Movement , Hep G2 Cells , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Lung Neoplasms/metabolism , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Mice , Mice, Nude , Neoplasm Invasiveness , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptor, Notch1/metabolism , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND This study investigated the molecular mechanism of the effect of CD44 on the recurrence of EGC after ESD, including the potential regulator and signaling pathways of CD44. MATERIAL AND METHODS We searched the miRNA online database (www.mirdb.org) with the "seed sequence" located within the 3'-UTR of the target gene, and performed luciferase assay to test the miRNA/mRNA relationship. We also determined the expression of CD44 in the EGC and control samples. In addition, statistical analysis was used to explore the role of miR-328 as a biomarker to predict the recurrence after ECD. RESULTS We validated CD44 to be the direct gene via luciferase reporter assay system. We also established the negative regulatory relationship between miR-328 and CD44 via studying the relative luciferase activity at different concentrations of miR-328 mimics. We also conducted real-time PCR and Western blot analysis to study the mRNA and protein expression level of CD44 among different groups (recurrence-positive and recurrence-negative) or cells treated with different concentrations of miR-328 mimics/inhibitors, indicating the negative regulatory relationship between miR-328 and CD44. We also investigated the relative viability of EGC cells when transfected with miR-328 mimics (50 nM and 100 nM) and miR-328 inhibitors (100 nM) to validate miR-328 to be negatively interfering with the viability of EGC cells. miR-328 was also recognized as a potential biomarker to predict recurrence after ESD in EGC patients via analysis of the recurrence-free rate among different groups of EGC patients. CONCLUSIONS The expression level of miR-328 can function as a predictive biomarker of recurrence after ECD in patients with EGC via targeting CD44.
