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Hepatitis B virus (HBV) has an important role in the development of human hepatocellular carcinoma (HCC). Accumulated evidence has shown that HBV-encoded X protein (HBx) can induce both genetic alterations in tumor suppressor genes and oncogenes, as well as epigenetic aberrations in HCC pathogens. Non-coding RNAs (ncRNAs) mainly include microRNAs and long non-coding RNAs (lncRNAs). Although ncRNAs cannot code proteins, growing evidence has shown that they have various important biological functions in cell proliferation, cell cycle control, anti-apoptosis, epithelial–mesenchymal transition, tumor invasion and metastasis. This review summarizes the current knowledge regarding the mechanisms and emerging roles of ncRNAs in the pathogenesis of HBV-related HCC. Accumulated data have shown that ncRNAs regulated by HBx have a crucial role in HBV-associated hepatocarcinogenesis. The findings of these studies will contribute to more clinical applications of HBV-related ncRNAs as potential diagnostic markers or as molecular therapeutic targets to prevent and treat HBV-related HCC.
Subject(s)
Humans , Carcinoma, Hepatocellular , Cell Cycle Checkpoints , Cell Proliferation , Epigenomics , Genes, Tumor Suppressor , Hepatitis B virus , Hepatitis B , Hepatitis , MicroRNAs , Neoplasm Metastasis , Oncogenes , RNA, Long Noncoding , RNA, UntranslatedABSTRACT
Colorectal carcinoma ( CRC ) is one of the malignant tumors with the highest morbidity and mortality rates in the world.The invasion and metastasis of CRC are the major reasons for treatment failure and death .It was believed that CXCR 4 was the exclusive receptor for CXCL12.However, recent studies have identified CXCR7 as a second receptor for CXCL12.Both chemokine ax-es of CXCL12/CXCR4 and CXCL12/CXCR7 closely correlate with the proliferation , migration, adhesion of tumor cells and the forma-tion of tumor-associated vessels in CRC , which may become new significant targets for anti-cancer and anti-metastatic treatment of CRC.
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<p><b>OBJECTIVE</b>To study the methylation changes in promoter CpG islands induced by low-dose X-ray radiation (LDR).</p><p><b>METHODS</b>Twenty male BALB/c mice were randomly divided into control and fractionated radiation group exposed to 6 MV X-ray for 10 days (0.05 Gy/day). All the mice were sacrificed 2 h after the last radiation on day 10, and blood samples were collected for detecting DNA methylation changes using Roche-NimbleGen mouse DNA methylation 3×720K Promoter Plus CpG Island Array. MeDIP-qPCR was used to further validate the methylation status of specific genes.</p><p><b>RESULTS</b>A total of 811 genes were found to show specific hypermethylation in fractional radiation group as compared with the control group, involving almost all the main biological processes by GO analysis. Eight candidate genes (Rad23b, Tdg, Ccnd1, Ddit3, Llgl1, Rasl11a, Tbx2, and Slc6a15) were confirmed to be hypermethylated in LDR samples by MeDIP-qPCR, consistent with the results of the methylation chip study.</p><p><b>CONCLUSION</b>LDR induces promoter hypermethylation on specific genes, which may contribute to radiation-induced pathogenesis.</p>
Subject(s)
Animals , Male , Mice , CpG Islands , Radiation Effects , DNA Methylation , Dose-Response Relationship, Radiation , Genome , Mice, Inbred BALB C , X-RaysABSTRACT
[Abstract ] Forkhead box(Fox) M1, as a member of the Fox transcription factor family, overexpresses in many kinds of canc-ers and is related to a variety of oncogenic signaling pathways.It plays an important role in the occurrence, progression and metastasis of cancer.FoxM1 has been a new target for cancer therapy research.
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Objective To investigate the role of epigallocatechin gallate ( EGCG) in reversing the CpG island methylation of Rad23b and Ddit3 gene promoter and its mRNA expression induced by 0?5 Gy X-rays. Methods Thirty BALB/c male mice were randomly divided into 6 groups: control group, irradiation group, low/high dose of EGCG group, low/high dose of EGCG with irradiation group. For the irradiation group, mice were fractionally exposed with 6 MV X-rays for 10 d (0?05 Gy/d × 10 d). 2 hours after the final irradiation, all mice were killed and such tissues as blood, kidney, liver, spleen, brain, and lung were collected. Methylation and expression levels of Rad23b and Ddit3 were measured by bisulfate sequencing primers ( BSP) and Real-time PCR, respectively. Results Compare to the control group, Rad23b was hypermethylated in PBMC, liver, spleen, brain and lung (t= -20?19, -14?80, -12?05,-28?42, -12?58, P<0?05) in the irradiation group. Meanwhile, its mRNA expression level was down-regulated in PBMC, liver, brain and lung (t=25?25, 17?43, 11?53, 22?85, P<0?05). Similarly, a significant hypermethylation change of Ddit3 was observed in PBMC, liver and lung after irradiation ( t=-52?89, -20?31, -3?85, P<0?05) so that the mRNA expression of Ddit3 decreased in PBMC and liver ( t = 11?89, 16?52, P < 0?05 ). Compared to the irradiation group, EGCG with different concentrations of 10, 20 mg/kg significantly reduced the methylation level of Rad23b and Ddit3 ( t =-13?39-7?99, P<0?05), and induced re-expression of mRNA (t= -34?02 - -2?89, P<0?05). This change was more notable in the irradiation group with the high dose of EGCG. Conclusions As a natural drug, EGCG may play an important role in affecting DNA methylation and hence protects DNA from radiation damage.
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Objective The invasion and metastasis of colon cancer often leads to treatment failure and mortality in patients . Our research is to investigate the influence of FoxM 1 to malignant human colon cancer line . Methods In two human colon cancer lines, the protein and mRNA expression levels of FoxM 1 were analyzed with the application of RT-PCR and Western blot , from which high-expressed HT-29 and low-expressed HCT-116 were determined.The expression of FoxM1 was down-regulated by RNA interfering in HT-29 and up-regulated by constructing overexpression transgenic line in HCT-116.The proliferation of the above cells was assayed by healing method;while the metastasis and invasion ability were examined by Transwell chamber assay . Results Two colon cancer lines were selected with high-expression or low-expression of FoxM1 separately named HT-29 and HCT-116.Application of PEX-2-FoxM1 raised after HCT-116 cells express FoxM1, cell scratches in HCT-116 experimetal group ([70.92 ±1.48]%) compared with HCT-116 control group([16.92 ±4.05]%)and HCT-116 blank control group([16.66 ±2.63]%) will markedly enhance its capabil-ity of healing (P<0.05), Transwell Chambers in membrane cells in HCT-116 experimetal group (186.0 ±6.8) compared with HCT-116 control group(42.0 ±2.0) and HCT-116 blank control grou (37.0 ± 2.2)was increased (P<0.05).On the other hand, the applied pG-PH-shFoxM1 can reduce FoxM1 expression in HT-29 cell, cell scrat-ches healing ability in HT-29 experimetal group ( [ 10 .37 ± 3.86]%) compared with HT-29 control group([34.63 ±2.35]%)and HT-29 blank control group([67.36 ±2.61]%) decreased significantly (P<0.05), Transwell Chambers in membrane cells in HT-29 experimetal group (53.0 ±1.8)compared with HT-29 control group(95.0 ±2.2)and HT-29 blank control grou(118.0 ±4.0) was also reduced (P<0.05). Conclusion The expression of FoxM1 is in close relation to the invasion and metastasis of CRC .The fact that the siRNA interfering FoxM1 could effectively inhibit the proliferation, metastasis and invasion, suggesting FoxM1 could po-tentially be a new molecular target for inhibiting the proliferation of human colon cancer line .
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Objective To study the whole genome DNA methylation changes induced by low dose radiation (LDR) in mouse,and mRNA expression profiles of DNMT1 and MBD2 in peripheral blood mononuclear cell (PBMC) and tissues.Methods Thirty male BALB/c mice were randomly divided into 3 groups:control,single exposure (0.5 Gy),and fractionated exposure of 6 MV X-rays for 10 d (0.05 Gy/d × 10 d).Control mice were sham-treated.To determine the immediate (early) effect of irradiation,15 mice (5/group) were sacrificed 2 h after the last irradiation.The other 15 mice were sacrificed 1 month after the last irradiation (delayed effect).Before sacrifice,blood was sampled immediately.Kidney,liver,spleen,brain and lung tissues were collected.A global DNA methylation quantification Kit and highperformance liquid chromatography (HPLC) were used to investigate the methylation level in blood DNA.The expressions of DNMT1 and MBD2 were determined by RT-PCR.Results For the early effects of irradiation,as compared with controls,fractionated exposure to X-ray irradiation led to the significant depression of global DNA methylation level in blood (t =10.19 and 8.93,P ＜ 0.05).DNMT1 and MBD2 mRNA were down-regulated in PBMC,kidney and liver (t =5.06,3.01,3.97,12.25,3.50 and 3.73,P ＜0.05),and MBD2 was also down-regulated in spleen (t =3.03,P ＜ 0.05).However,no changes were observed in single exposed group.As for the delayed effects,the methylation levels of blood were not changed in the single or fractionated exposed groups,and only MBD2 mRNA was down-regulated in PBMC and brain of fractionated exposed group (t =3.52 and 2.85,P ＜ 0.05).Conclusions Fractionated LDR exposure can induce genome DNA hypomethylation,which is tissue-specific,and may be related with down-regulation of DNMT1 and MBD2.
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Objective:To investigate specific activity of cytotoxic T lymphocyte(CTL) induced by(mIL-12) gene modified dendritic cells(DCs) transfected with the total RNA of CT-26(a cell line of murine carcinoma of colon).Methods:In vitro proliferation of DCs from the culture of murine bone marrow was stimulated by rmGM-CSF and rmIL-4,and the purity of DCs was detected by flow-cytometry.The generated DCs were then modified by adenovirus with mIL-12 gene which were proliferated in 293 cells.The total RNA of CT-26 was obtained through Trizol's process,and transfected into the mIL-12 gene modified DC by TransMessenger in vitro.The levels of mIL-12 both in vitro and in vivo and the activity of CTL in vivo were estimated with enzyme linked immunosorbent assay and modified lactate dehydrogenase release assay respectively.Results:Plenty of DCs were obtained from the culture of murine bone marrow,with over 90 % of CD11c~(+) cells.DC modified by mIL-12 gene could induce high level of mIL-12 both in vitro and in vivo,and the differences compared to control groups were significant(P
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Objective: Recent researches suggest that tumors are organized in a hierarchy of heterogeneous cell populations and that the capability of maintaining tumor formation/growth specifically resides in a small population of cells called cancer stem cells(CSCs).CSCs are resistant to traditional cancer chemotherapy and radiation therapy because they highly express ATP-binding cassette(ABC) drug transporters and are relatively quiescent,with higher DNA repair and anti-apoptosis abilities.The purpose of this study is to investigate the relationship of ABC transporters with the multi-drug resistance and cancer stem cells of SPC-A1 cell lines.Methods: On the basis of Docetaxel-resistant cell line-SPC-A1/ Docetaxel,we compared the content and biological characteristics of SP cells,the expression of ABC transporters and its effect on the multi-resistance to Docetaxel between SPC-A1 and SPC-A1/ Docetaxel cell lines.Results: SP cells existed in both the SPC-A1 and the SPC-A1/ Docetaxel cell line,with a higher content in the latter.P-gp and BCRP obviously expressed in the SPC-A1/ Docetaxel and SPC-A1/ Docetaxel-SP cells,but only the expression of BCRP was increased in SPC-A1-SP cells.SPC-A1-SP cells also showed obviously higher abilities of proliferation,cloning and tumor formation than SPC-A1/ Docetaxel-SP cells.The multi-drug resistance of SPC-A1/ Docetaxel cells could be reversed with verapamil,but their resistance to Docetaxel could not be reversed completely with the same concentration of the drug.Conclusion: BCRP plays a major role in separating SP cells with tumor stem cell traits and its expression counts for the multi-drug resistance of SPC-A1-SP cells.
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Objective:Position emission tomography/computed tomography(PET/CT) is a new bio-imaging system which is combined metabolic with anatomic imaging.This study was to compare the accuracy of conventional staging methods(including computed tomography,ultrasound,magnetic resonance imaging,and detection of bone marrow) with that of PET/CT for lymphoma staging and re-staging. Methods:A total of 42 patients with lymphoma diagnosed by operation or biopsy,received conventional and PET/CT staging.The accuracy of these two methods and their impact on lymphoma staging were compared.Results:The accuracy of PET/CT scan was 95.2%(40/42),and that of conventional staging was 78.6%(33/42).The detection rates of internal lymph node were 97.1%(66/68) and 88.2%(60/68),respectively.The detection rates of outer lymph node were 91.7%(22/24) and 58.3%(14/24),respectively.Compared with conventional staging methods,7 cases were up-staged and 2 cases were down-staged by PET/CT,which led to the change of therapy in 8 cases.Conclusion:PET/CT scan is more sensitive and accurate than conventional staging methods in staging and restaging of lymphoma.
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Objective:To observe the recent effects and toxicity of thermochemotherapy on malignant hydrothorax or hydroperitoneum,to evaluate the changes of the immunological functions,and to investigate the mechanism of thermochemotherapy.Methods:Fifty-two patients were treated with weekly intracavitary chemotherapy,and then combined with local endogenetic thermotherapy twice a week.As the control,another 50 patients received weekly intracavitary chemotherapy.The treatment lasted for two weeks and was followed by one-week rest,and then the recent effects and toxicity were observed.The T cell subset,NK cells and VEGF levels in serum,hydrothorax or hydroperitoneum were tested.Results:Overall response rates of the malignant hydrothorax were 86.9% vs 60.0%(P