Poster Session:PS 0234 ; Gastroenterology : Effect of Mir-34a in Regulating Steatosis by Targeting PPARa Expression in NAFLD

( Jie Xia Ding ),( Meng Li ),( Xi Jin ),( Shao Hua Chen ),( Chao Hui Yu ),( You Ming Li ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Background: The association between altered expression of miR-34a and pathophysiological features of nonalcoholic fatty liver disease (NAFLD) and whether there is a connection between susceptibility to NAFLD has not been completely clarifi ed. Methods: The vitro model was established by culturing L02 cells with a high concentration of free fatty acid (FFA) and the vivo model was established by feeding C57BL/6 mice with HFD. To determine the effects of miR-34a, cultured L02 cells transfected with miR-34a inhibitor and C57BL/6 mice injected with miR-34a inhibitor through vein tail were analysed for the level of PPARaand the metabolic sensor AMPK. In functional experiments, TG content and steatosis degree were measured by TG assay kit, HE and Oil Red O staining. Results: miR-34a expression is signifi cantly upregulated in steatosis-induced hepatocytes and in liver tissues of HFD fed mice. The upregulation of miR-34a resulted in the downregulation of hepatic peroxisome proliferator-activated receptor-a(PPARa), the direct target of miR-34a. Moreover, the action of miRNA-34a on PPAR-a depends on the presence of a single miRNA-34a binding site. Silencing miR-34a led to an initial increase the level of PPARaand the targets of PPARa, including CPT1, CPT2, SLC27A4, SLC27A1 and ACBD3. Activation of the central metabolic sensor AMPK was also increased. In functional experiments, miR-34a inihibitor suppressed cell and mice liver TG content and improve steatosis degree. Furthermore, inhibition of PPARa expression aggravated hepatocellular steatosis in vitro models. Conclusions: NAFLD is associated with altered hepatic miR-34a expression. Decreased expression of miR-34a potentially contributes to altered lipid metabolism implicated in the pathogenesis of NAFLD. These results suggest that regulating it`s target PPARa by down-regulation of miR-34a levels may be a therapeutic strategy against NAFLD.

Poster Session:PS 0235 ; Gastroenterology : Hadha Plays a Role of Double-Edged Sword in Hepatic Steatosis and Cell Injury in Nonalcoholic Fatty Liver Disease

( Jie Xia Ding ),( Meng Li ),( Xing Yong Wan ),( Xi Jin ),( Shao Hua Chen ),( Chao Hui Yu ),( You Ming Li ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Background: The mechanisms of pathogenesis underlying nonalcoholic fatty liver disease (NAFLD) remain unclear at present and the depth study of HADHA in the development of NAFLD has never been investigated. Methods: The NAFLD cell model was established by treating L02 cells with free fatty acid (FFA) overload. Small interfering RNA (siRNA) was used to knock down HADHA level. The expression of HADHA and key enzymes associated with fatty acid beta- oxidation in L02 cells were determined by q-PCR. Key protein associated in energy metabolism, endoplasmic reticulum(ER) stress and infl ammatory were determined by western blotting. ATP, hydroperoxide (H2O2), catalase (CAT) and mitochondrial membrane potential (MMP) were measured. The prediction of HADHA upstream regulation of miRNA was carried out and luciferase reporter assays were implemented to validate the prediction. Results: After culturing L02 cells by FFA for 48h, we detect the increased protein level of HADHA. HADHA knockdown in L02 cells resulted in an increased of lipid accumulation and downregulation of gene expression involved in fatty acid beta-oxidation, including PPARa, ACOX1, CPT2, EHHADH, ECHS1, HADHB and HADH. Additionally, administering HADHA siRNA exhibited improvement of oxidative stress, embodied in decreased level of H2O2 and MDA, meanwhile, increased levels of ATP, CAT and MMP. Furthermore, HADHA knockdown demonstrated weakened AMPK pathway, activation of MAPK and MKK3 pathway, and improve ER stress by downregulation of C/EBPa and C/EBPß. Moreover, HADHA was regulated directly by upstream gene of miR-124. Conclusions: Our results show that HADHA may plays a role of double-edged sword in hepatic steatosis and cell injury in NAFLD, and provide a new insight into the pathogenic mechanisms of NAFLD, may becoming a potential new therapeutic target for NAFLD.

Expression Characteristics of Proteins of the Insulin-like Growth Factor Axis in Non-small Cell Lung Cancer Patients with Preexisting Type 2 Diabetes Mellitus

Ding, Jing,Tang, Jie,Chen, Xin,Men, Hai-Tao,Luo, Wu-Xia,Du, Yang,Ge, Jun,Li, Cong,Chen, Ye,Cheng, Ke,Qiu, Meng,Liu, Ji-Yan Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.10

Background: Preexisting type 2 diabetes mellitus (T2DM) affects the prognosis and mortality of patients with some cancers. Insulin like growth factor (IGF) and insulin receptor (IR) signaling axes play important roles in both cancer and diabetes development. We aimed to explore the expression characteristics of proteins in IGF/IR axis in non-small cell lung cancer (NSCLC) cases with preexisting T2DM. Methods: Fifty-five NSCLC patients with preexisting T2DM were retrospectively included and matched by 55 NSCLC without diabetes at a 1:1 ratio. The expression of proteins in IGF/IR axis was detected by immunohistochemical staining. Clinicopathological data were collected to analyze their relationship with the protein expression. Results: Both IGF 1 receptor (IGF-1R) and insulin receptor substrate 2 (IRS-2) showed higher expression in the NSCLC with T2DM group, compared with those without T2DM. The high expression of IGF-1R and IRS-2 were found to be negatively associated with lymph node metastases and T staging in the T2DM group, respectively, and IRS-2 expression was also found more in the subgroup whose T2DM duration was more than 4 years. No difference was detected in the expression of IRS-1, IGF-1, IGF-2, IGFBP3, IR and mTOR between groups with or without T2DM. Conclusion: Our study found higher expression of IGF-1R and IRS-2 proteins in NSCLC patients with preexisting T2DM, and that there was an association with early stage NSCLC, which suggested that IGF signaling may play an important early event in development of NSCLC associated with diabetes.

Expression of the CXCL12/SDF-1 Chemokine Receptor CXCR7 in Human Brain Tumours

Tang, Tian,Xia, Qing-Jie,Chen, Jian-Bin,Xi, Ming-Rong,Lei, Ding Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.10

Purpose: Receptor 7 (CXCR7) has recently been characterized as a novel receptor for CXCL12/SDF-1 (stromal cell derived factor-1). Given the demonstrated importance of CXCL12/SDF-1 in angiogenesis and tumour metastasis, we hypothesized that CXCR7 may also play a role in tumour pathogenesis. Located in the limited space of the intracranial cavity, any brain tumours can be inherently serious and life-threatening. However, the expression of CXCR7 in pituitary adenoma, neurilemmoma or hemangioblastoma remains to be elucidated. Therefore, we aimed to determine the potential contribution of CXCR7 in the development of brain tumours. Methods: In this study we examined and quantified the mRNA expression of CXCR7 in four different human brain tumours - 27 patients with neurilemmoma (8 patients), pituitary adenoma (7 patients), hemangioblastoma (6 patients), or meningioma (6 patients) undergoing surgical resection in the West China Hospital of Sichuan University. There were 15 females and 12 males aged from 28 to 70 years old. Total RNA was isolated and mRNA was measured by quantitative real-time RT-PCR. One-way analysis of variance (ANOVA) was performed using SPSS 11.0 statistical software to compare the mRNA levels of CXCR7 among four groups. Results: We found that CXCR7 mRNA was detected in all tumour samples. Quantitative results showed that the levels of CXCR7 mRNA in brain tissues from patients with neurilemmoma or meningioma were significantly higher than those with pituitary adenoma or hemangioblastoma. Conclusions: The results suggest that the CXCR7 may play a role in progression, metastasis and angiogenesis of brain tumours.

Folate Deficiency and FHIT Hypermethylation and HPV 16 Infection Promote Cervical Cancerization

Bai, Li-Xia,Wang, Jin-Tao,Ding, Ling,Jiang, Shi-Wen,Kang, Hui-Jie,Gao, Chen-Fei,Chen, Xiao,Chen, Chen,Zhou, Qin Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.21

Fragile histidine triad (FHIT) is a suppressor gene related to cervical cancer through CpG island hypermethylation. Folate is a water-soluble B-vitamin and an important cofactor in one-carbon metabolism. It may play an essential role in cervical lesions through effects on DNA methylation. The purpose of this study was to observe effects of folate and FHIT methylation and HPV 16 on cervical cancer progression. In this study, DNA methylation of FHIT, serum folate level and HPV16 status were measured using methylation-specific polymerase chain reaction (MSP), radioimmunoassay (RIA) and polymerase chain reaction (PCR), respectively, in 310 women with a diagnosis of normal cervix (NC, n=109), cervical intraepithelial neoplasia (CIN, n=101) and squamous cell carcinoma of the cervix (SCC, n=101). There were significant differences in HPV16 status (${\chi}^2=36.64$, P<0.001), CpG island methylation of FHIT (${\chi}^2=71.31$, P<0.001) and serum folate level (F=4.57, P=0.011) across the cervical histologic groups. Interaction analysis showed that the ORs only with FHIT methylation (OR=11.47) or only with HPV 16 positive (OR=4.63) or with serum folate level lower than 3.19ng/ml (OR=1.68) in SCC group were all higher than the control status of HPV 16 negative and FHIT unmethylation and serum folate level more than 3.19ng/ml (OR=1). The ORs only with HPV 16 positive (OR=2.58) or with serum folate level lower than 3.19ng/ml (OR=1.28) in CIN group were all higher than the control status, but the OR only with FHIT methylation (OR=0.53) in CIN group was lower than the control status. HPV 16 positivity was associated with a 7.60-fold increased risk of SCC with folate deficiency and with a 1.84-fold increased risk of CIN. The patients with FHIT methylation and folate deficiency or with FHIT methylation and HPV 16 positive were SCC or CIN, and the patients with HPV 16 positive and FHIT methylation and folate deficiency were all SCC. In conclusion, HPV 16 infection, FHIT methylation and folate deficiency might promote cervical cancer progression. This suggests that FHIT may be an effective target for prevention and treatment of cervical cancer.

Down-regulation of FRα Inhibits Proliferation and Promotes Apoptosis of Cervical Cancer Cells in Vitro

Bai, Li-Xia,Ding, Ling,Jiang, Shi-Wen,Kang, Hui-Jie,Gao, Chen-Fei,Chen, Chen,Zhou, Qin,Wang, Jin-Tao Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.14

Folate receptor alpha ($FR{\alpha}$) mediates folate uptake by endocytosis, and while folate is essential to DNA methylation and synthesis and may have an important role in proliferating cells. $FR{\alpha}$ is known to be expressed in rapidly proliferating cells, including many cancer cell lines, but there has been no systematic assessment of expression in cervical cancer cell lines. The aim of the present study was to evaluate the effects of $FR{\alpha}$ on proliferation and apoptosis of cervical cells and correlation mechanism. In this study, we investigated the biological function of $FR{\alpha}$ in Hela cells using RNA interference. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK8) assay, while cell cycling and apoptosis were assessed by flow cytometry, mRNA levels by real time-PCR and protein levels of $FR{\alpha}$, c-Fos and c-Jun by Western blotting. The results revealed that $FR{\alpha}$ was highly expressed in Hela cells and its silencing with a small interfering RNA (siRNA) inhibited cell proliferation and induced cell apoptosis, arresting the cell cycle in G0/G1 stages while decreasing the proportion in S and G2/M stages, and suppressed the expression levels of c-Fos and c-Jun. In conclusion, the results of this study indicated that $FR{\alpha}$ down-regulation might be capable of suppressing cervical cancer cell proliferation and promoting apoptosis. It suggested that $FR{\alpha}$ might be a novel therapeutic target for cervical cancer.

Postmenopausal Hormone Therapy is Associated with in Situ Breast Cancer Risk

Ni, Xiao-Jian,Xia, Tian-Song,Zhao, Ying-Chun,Ma, Jing-Jing,Zhao, Jie,Liu, Xiao-An,Ding, Qiang,Zha, Xiao-Ming,Wang, Shui Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.8

Background: The relationship between postmenopausal hormone therapy (HT) and invasive breast cancer has been extensively investigated, but that with breast carcinoma in situ (BCIS) has received relatively little attention. The aim of our present study was to review and summarize the evidence provided by longitudinal studies on the association between postmenopausal HT use and BCIS risk. Methods: A comprehensive literature search for articles published up to May 2012 was performed. Prior to performing a meta-analysis, the studies were evaluated for publication bias and heterogeneity. Relative risk (RR) or odds ratio (OR) values were calculated using 14 reports (8 case-control studies and 6 cohort studies), published between 1986 and 2012. Results: There was evidence of an association between ever postmenopausal estrogen use and BCIS based on a random-effects model (RR = 1.25, 95% confidence interval (CI) = 1.01, 1.55). However, we found no strong evidence of an association between ever postmenopausal estrogen combined with progesterone use and BCIS using a randomeffects model (RR = 1.55, 95% CI = 0.95, 2.51). Furthermore, our analysis showed a strong association between "> 5 years duration" of estrogen or estrogen combined with progesterone use and BCIS. Furthermore, current use of any HT is associated with increased risk of BCIS in cohort studies. Additional well-designed large studies are now required to validate this association in different populations.

Serum Carbohydrate Antigen 19-9 as an Indicator of Liver Metastasis in Colorectal Carcinoma Cases

Dong, Hang,Tang, Jie,Li, Long-Hao,Ge, Jun,Chen, Xin,Ding, Jing,Men, Hai-Tao,Luo, Wu-Xia,Du, Yang,Li, Cong,Zhao, Feng,Chen, Ye,Cheng, Ke,Liu, Ji-Yan Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.2

Purpose: The liver is the organ to which colorectal carcinomas (CRCs) most commonly metastasize, and surgical resection has been established as the most effective and potentially curative treatment for CRC with liver metastasis (LM). Therefore, surveillance of LM is vital for improvement of prognosis of CRC patients. In this study, we aimed to explore the potential value of carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), and marker enzymes in indicating LM with CRC. Methods: Three groups of eligible patients with metastatic cancers were retrospectively included: CRC patients with LM (CRC-LM) or without LM (CRC-NLM), and non-CRC patients with LM (NCRC-LM). All metastatic lesions were identified by CT or MRI. Data on characteristics of the patients, the primary site, the locations of metastasis, CA 19-9, CEA, and biochemical parameters were collected for analysis. Results: A total of 493 patients were retrospectively included. More alcohol consumption was found in CRC-LM than CRC-NLM. Some biochemical enzymes were found to be significantly higher in groups with LM than without (CRC-LM or NCRC-LM v.s CRC-NLM). Both CEA and CA 19-9 were much higher in CRC-LM than CRC-NLM or NCRC-LM. For CRC patients, CA 19-9, ${\gamma}$-glutamyl transpeptidase, CEA and alcohol consumption were identified as independent factors associated with LM. Conclusion: Our analysis suggested the CA 19-9 might be a potential valuable indicator for LM of CRC in the clinic.

Case Reports : Surgical Treatment for 11 Cases of Penile Verrucous Carcinoma

( Chuan Yu Sun ),( Xu Ke ),( Zheng Jie ),( Guo Wei Xia ),( Zu Jun Fang ),( Qiang Ding ) 대한피부과학회 2011 Annals of Dermatology Vol.23 No.3s

Penile verrucous carcinoma is a rare, well-differentiated and low-grade tumor. The surgeons are deficiently aware about the biological behavior and the clinicopathological characteristic of this disease, which raises difficulties during the treatment. In our present study, the clinical and pathological data of 11 patients with penile verrucous carcinoma, aged between 49 to 85 years was retrospectively analyzed. The tumors exhibited exophytic, papillary, caulifower-like or verrucose lesions of great dimensions measuring between 2 to 10 cm on the penises. The tumors were located at glans in 6 cases, invaded the coronoid sulcus in 4 cases and invaded the shaft of the penis in 1 case. Eight cases underwent partial penectomy, while the other 3 were treated with local excision. The diagnosis of penile verrucous carcinoma was confirmed by histopathologic examination of the specimens with the negative surgical margins in all the cases. Within the period of 12 to 60 months of follow-up, all the patients were disease-free with no case of recurrence and metastasis. The novel knowledge and experience of the treatment of penile verrucous carcinoma will be a useful clinical guide for surgeons in the future. (Ann Dermatol 23(S3) S346~S349, 2011)

Surgical Treatment for 11 Cases of Penile Verrucous Carcinoma

Sun Chuanyu,Xu Ke,Zheng Jie,Xia Guowei,Fang Zujun,Ding Qiang 대한피부과학회 2011 Annals of Dermatology Vol.23 No.-

Penile verrucous carcinoma is a rare, well-differentiated and low-grade tumor. The surgeons are deficiently aware about the biological behavior and the clinicopathological characteristic of this disease, which raises difficulties during the treatment. In our present study, the clinical and pathological data of 11 patients with penile verrucous carcinoma, aged between 49 to 85 years was retrospectively analyzed. The tumors exhibited exophytic, papillary, caulifower-like or verrucose lesions of great dimensions measuring between 2to 10 cm on the penises. The tumors were located at glans in 6 cases, invaded the coronoid sulcus in 4 cases and invaded the shaft of the penis in 1 case. Eight cases underwent partial penectomy, while the other 3 were treated with local excision. The diagnosis of penile verrucous carcinoma was confirmed by histopathologic examination of the specimens with the negative surgical margins in all the cases. Within the period of 12 to 60 months of follow-up, all the patients were disease-free with no case of recurrence and metastasis. The novel knowledge and experience of the treatment of penile verrucous carcinoma will be a useful clinical guide for surgeons in the future. (Ann Dermatol 23(S3) S346∼S349,2011)