MPHOSPH1: A Potential Therapeutic Target for Hepatocellular Carcinoma
Xinran LiuYafan ZhouXinyuan LiuAnlin PengHao GongLizi HuangKaige JiRobert B. PetersenLing ZhengKun Huang
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Abstract:
MPHOSPH1 is a critical kinesin protein that functions in cytokinesis. Here, we show that MPHOSPH1 is overexpressed in hepatocellular carcinoma (HCC) cells, where it is essential for proliferation. Attenuating MPHOSPH1 expression with a tumor-selective shRNA-expressing adenovirus (Ad-shMPP1) was sufficient to arrest HCC cell proliferation in a manner associated with an accumulation of multinucleated polyploid cells, induction of postmitotic apoptosis, and increased sensitivity to taxol cytotoxicity. Mechanistic investigations showed that attenuation of MPHOSPH1 stabilized p53, blocked STAT3 phosphorylation, and prolonged mitotic arrest. In a mouse subcutaneous xenograft model of HCC, tumoral injection of Ad-shMPP1 inhibited MPHOSPH1 expression and tumor growth in a manner correlated with induction of apoptosis. Combining Ad-shMPP1 injection with taxol administration enhanced antitumor efficacy relative to taxol alone. Furthermore, Ad-shMPP1 tail vein injection suppressed formation of orthotopic liver nodules and prevented hepatic dysfunction. Taken together, our results identify MPHOSPH1 as an oncogenic driver and candidate therapeutic target in HCC.OBJECTIVE To explore the killing effect of IM 94 to human hepatocellular carcinoma cells. METHOD MTT method was used to analyse the influence of IM 94 on human hepatocellular carcinoma. Flow cytometry was applied to detected the mitosis cycle and cell apoptosis , and karyoschisis was analysed by HE staining.RESULTS IM 94 has obvious inhibitory effect on hepatocellular carcinoma cells. Cell was blocked at G2+M stages, and cell apoptosis was induced. A small apoptosis spike was appeared in 24 hours.CONCLUSION IM 94 can block mitosis and induce apoptosis of hepatocellular carcinoma cells.
MTT assay
Hepatic carcinoma
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Hepatocellular carcinoma is the most common type of liver cancer. Radiotherapy combined with chemotherapy is the treatment of choice for hepatocellular carcinoma, but radioresistance of the cancer remains a significant therapeutic hindrance. Here, we provided several lines of evidence that small ubiquitin-like modifier (SUMO)-specific protease 6 (SENP6) could be an attractive molecular target for the treatment of hepatocellular carcinoma. By using immunohistochemical and real-time PCR, we showed that SENP6 was overexpressed in more than half of the hepatocellular carcinoma tissues. The growth retardation and radiosensitization were caused by silencing of SENP6 in the hepatocellular carcinoma cell lines using lentiviral shRNA. Moreover, SENP6 was required for radiation-induced NF-κB activation and the half-life of IκBα, a well-known inhibitor of NF-κB, and was extended by SENP6 silencing. Thus, our data demonstrated that SENP6 is an attractive drug target for anticancer therapy and radiosensitization.
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To study the effects of EGCG on the proliferation and apoptosis and the expression of Singnal transducer and activator of transcription-3(Stat3) in human hepatocellular carcinoma cell line BEL-7402.The effect of different concentrations of GECG on the proliferation was detected by MTT assay.The Flow cytometric analysis was performed to detect the cell apoptosis.ELISA assay was applied to test the expression of Stat3 and phosphorylation Stat3.EGCG could inhibit proliferation and induce apoptosis in a dose dependent manner in BEL-7402 cells.Moreover,EGCG down-regulated the expression of phosphorylation Stat3.EGCG inhibits growth inhibition and induces apoptosis in human heptocellular carcinoma cell line BEL-7402 possibly by down-regulating p-Stat3 expression.
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Drug resistance is one of the major concerns in the treatment of hepatocellular carcinoma (HCC). The aim of the present study was to determine whether aberrant high expression of the inhibitor of differentiation 1(ID1) confers oxaliplatin-resistance to HCC by activating the pentose phosphate pathway (PPP).Aberrant high expression of ID1 was detected in two oxaliplatin-resistant cell lines MHCC97H-OXA(97H-OXA) and Hep3B-OXA(3B-OXA). The lentiviral shRNA or control shRNA was introduced into the two oxaliplatin-resistant cell lines. The effects of ID1 on cell proliferation, apoptosis and chemoresistance were evaluated in vitro and vivo. The molecular signaling mechanism underlying the induction of HCC proliferation and oxaliplatin resistance by ID1 was explored. The prognostic value of ID1/G6PD signaling in HCC patients was assessed using the Cancer Genome Atlas (TCGA) database.ID1 was upregulated in oxaliplaitin-resistant HCC cells and promoted HCC cell proliferation and oxaliplatin resistance. Silencing ID1 expression in oxaliplaitin-resistant HCC cell lines inhibited cell proliferation and sensitized oxaliplaitin-resistant cells to death. ID1 knockdown significantly decreased the expression of glucose-6-phosphate dehydrogenase (G6PD), a key enzyme of the PPP. Silencing ID1 expression blocked the activation of G6PD, decreased the production of PPP NADPH, and augmented reactive oxygen and species (ROS), thus inducing cell apoptosis. Study of the molecular mechanism showed that ID1 induced G6PD promoter transcription and activated PPP through Wnt/β-catenin/c-MYC signaling. In addition, ID1/G6PD signaling predicted unfavorable prognosis of HCC patients on the basis of TCGA.Our study provided the first evidence that ID1 conferred oxaliplatin resistance in HCC by activating the PPP. This newly defined pathway may have important implications in the research and development of new more effective anti-cancer drugs.
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Abstract The oncogenic transcription factor Stat3 is constitutively active in a high percentage of human tumors including mammary adenocarcinomas and is reported to participate in the ErbB‐2 oncogene signaling. In order to assess the role of signal transducer and activator of transcription 3 (Stat3) in mammary tumorigenesis downstream of ErbB‐2, we generated mice expressing the activated rat ErbB‐2 (neu) but lacking Stat3 in the mammary epithelium. Stat3 is apparently not required for neu‐driven mammary tumorigenesis as tumors developed similarly in both Stat3‐sufficient and Stat3‐deficient glands. However, short hairpin RNA (shRNA)‐mediated Stat3 silencing in a neu‐overexpressing tumor‐derived cell line completely abolished both neu‐driven anchorage‐independent growth and lung metastasis. Our data suggest that Stat3 might be a useful therapeutic target in breast tumors showing amplification and/or overexpression of the ErbB‐2 oncogene, which normally display aggressive, metastatic behavior. © 2009 Wiley‐Liss, Inc.
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Glioblastoma multiforme (GBM) is characterized by an aggressive clinical course, therapeutic resistance, and striking molecular heterogeneity. GBM-derived brain tumor stem cells (BTSCs) closely model this molecular heterogeneity and likely have a key role in tumor recurrence and therapeutic resistance. Emerging evidence indicates that Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 is an important mediator of tumor cell survival, growth, and invasion in a large group of GBM. Here, we used a large set of molecularly heterogeneous BTSCs to evaluate the translational potential of JAK2/STAT3 therapeutics. BTSCs were cultured from GBM patients and MGMT promoter methylation, and the mutation statuses of EGFR, PTEN, and TP53 were determined. Endogenous JAK2/STAT3 activity was assessed in human GBM tissue, BTSCs, and orthotopic xenografts by immunohistochemistry and Western blotting. STAT3 short hairpin (sh)RNA, cucurbitacin-I, and WP1066 were used to inhibit JAK2/STAT3 activity in vitro and in vivo. The JAK2/STAT3 pathway was demonstrated to be highly activated in human GBM, molecularly heterogeneous BTSCs derived from these tumors, and BTSC xenografts. STAT3 shRNA knockdown or cucurbitacin-I and WP1066 administration resulted in on-target JAK2/STAT3 inhibition and dramatically reduced BTSC survival regardless of endogenous MGMT promoter methylation or EGFR, PTEN, and TP53 mutational status. BTSC orthotopic xenografts maintained the high levels of activated JAK2/STAT3 seen in their parent human tumors. Intraperitoneal WP1066 reduced intratumoral JAK2/STAT3 activity and prolonged animal survival. Our study demonstrates the in vitro and in vivo efficacy of on-target JAK2/STAT3 inhibition in heterogeneous BTSC lines that closely emulate the genomic and tumorigenic characteristics of human GBM.
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Abstract Hepatocellular carcinoma (HCC) is a more common malignancy than the majority of cancers and ranks second in the world’s top causes of cancer-related mortality. The objective of the study was to investigate and explain how circularRNA-9119 (circ9119) regulated the properties of HCC cell lines. Cancer cells isolated from HCC patients and HCC cell lines showed clearly upregulated expression of circ9119 and Janus kinase 1 (JAK1) with decreased levels of miR-26a compared to healthy controls and normal hepatic cells. To determine the function of circ9119, circ9119 was silenced in HCC cells, resulting in significantly less proliferation of HCC cells and increasing apoptosis. Circ9119 silencing also resulted in the upregulation of miR-26a. Bioinformatics prediction and dual-luciferase reporter assays showed that circ9119 targeted miR-26a. Further studies revealed that miR-26a had the opposite effect on circ9119; the inhibition of miR-26a antagonized circ9119 silencing, leading to reduced cell proliferation and increased apoptosis, while the ectopic overexpression of miR-26a impaired cell growth. Additionally, we found that the JAK1 3′-UTR was targeted by miR-26a; a decrease in the levels of JAK1 protein and mRNA followed transfection of a miR-26a mimic. Administration of the JAK1 inhibitor, baricitinib, caused the activation of signal transducer and activator of transcription 3 (STAT3) and revealed an effect similar to that of circ9119 silencing on cell proliferation and apoptosis. These results showed that circ9119 could modulate apoptosis, and broadly, cell proliferation by competitively binding miR-26a, which targeted JAK1-STAT3, in HCC cell lines. This study is a novel description of circ9119 regulation of HCC.
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Abstract NUPR1 (nuclear protein 1) was found to play a key role in the development of several malignancies including pancreas, breast, and prostate cancers. However, the functional role of NUPR1 in nonsmall cell lung cancer (NSCLC) progression and development is little known. Here, lentivirus‐mediated small interfering RNA (siRNA) was employed to downregulate endogenous NUPR1 expression to study the function of NUPR1 in growth of nonsmall cell lung cancer. A lentivirus‐mediated RNAi technology was used to specifically knock down the expression of NUPR1 in H1299 cells. Quantitative real‐time reverse transcriptase polymerase chain reaction, flow cytometry, western blot and cell count assays were studied to characterize NUPR1 expression in vitro . Furthermore, nonsmall cell lung cancer xenograft models in nude mice were established to investigate whether knockdown of NUPR1 reduces the tumor growth in vivo . We found that downregulation of NUPR1 expression significantly inhibited nonsmall cell lung cancer H1299 cells proliferation and colony formation in vitro . Moreover, the specific downregulation of NUPR1 arrested cells in G0 phase of cell cycle and increased apoptosis rate. Silencing of NUPR1 also suppressed tumor growth by tail vein injection of lentivirus encoded shRNA against NUPR1 in vivo . Our findings revealed that the NUPR1 gene represents a promising target for gene silencing therapy in nonsmall cell lung cancer. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.
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