SPON2 Promotes M1-like Macrophage Recruitment and Inhibits Hepatocellular Carcinoma Metastasis by Distinct Integrin–Rho GTPase–Hippo Pathways

Zhang, Yan-Li,Li, Qing,Yang, Xiao-Mei,Fang, Fang,Li, Jun,Wang, Ya-Hui,Yang, Qin,Zhu, Lei,Nie, Hui-Zhen,Zhang, Xue-Li,Feng, Ming-Xuan,Jiang, Shu-Heng,Tian, Guang-Ang,Hu, Li-Peng,Lee, Ho-Young,Lee, Su-J American Association for Cancer Research 2018 Cancer research Vol.78 No.9

<P>Matricellular protein SPON2 acts as an HCC suppressor and utilizes distinct signaling events to perform dual functions in HCC microenvironment.</P><P>Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signaling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-Actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2-α5β1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.</P><P><B>Significance:</B> Matricellular protein SPON2 acts as an HCC suppressor and utilizes distinct signaling events to perform dual functions in HCC microenvironment.</P><P><B>Graphical Abstract:</B> http://cancerres.aacrjournals.org/content/canres/78/9/2305/F1.large.jpg. <I>Cancer Res; 78(9); 2305–17. ©2018 AACR</I>.</P><P><B>Graphical Abstract</B></P><P> [Figure]</P>

Synthesis, Characterization, and Micellization of pH-Responsive Poly(4-vinylpyridine)-block-Poly(methacrylic acid) Four-Armed Star-Shaped Block Copolymers

Feng Xu,Shu-Zhen Zheng,Yan-Ling Luo,Ting-Ting Chen 한국고분자학회 2013 Macromolecular Research Vol.21 No.9

pH-sensitive poly(4-vinylpyridine)-block-poly(methacrylic acid) (P4VP-b-PMAA) four-armed starshaped block copolymers were synthesized by two-step atom transfer radical polymerization (ATRP), followed by hydrolysis of P4VP-b-poly(tert-butyl methacrylate) (P4VP-b-PtBMA). The chemical structure and molecular weight of the as-synthesized block copolymers were characterized by Fourier transform infrared spectrometry (FTIR), nuclear magnetic resonance (1H and 13C NMR), and gel permeation chromatography (GPC) determinations. The solution behavior was investigated by surface tension technique, ultraviolet visible (UV-vis) transmittance,transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potentials measurements. The experimental results indicated that the copolymers can spontaneously assemble into spherical-shaped core-shell micelle aggregates, with a critical micelle concentration (CMC) about 200 mg L-1, hydrodynamic diameters from 90to 210 nm, depending on the environmental pH values and compositional ratios. The transmittance measurements revealed that the block copolymers produce evident phase transition in aqueous solution at pH from 6.5 to 7.0. Zeta potential data revealed high micelle stability. The as-synthesized block copolymers are anticipated to find their applications in the realms of specific drug release, metal loading and heterogeneous catalysis.

Predictive and Prognostic Roles of Ribonucleotide Reductase M1 in Patients with Pancreatic Cancer Treated with Gemcitabine: A Meta-analysis

Zhang, Xiong,Jin, Fen-Shu,Zhang, Li-Guo,Chen, Rui-Xue,Zhao, Jin-Hui,Wang, Yan-Nan,Wang, En-Fu,Jiang, Zhen-Dong Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.7

Increasing scientific evidence suggests that ribonucleotide reductase M1 (RRM1) may be a powerful predictor of survival in patients with pancreatic cancer treated with adjuvant gemcitabine-based chemotherapy after operative resection, but many existing studies have yielded inconclusive results. This meta-analysis aimed to assess the prognostic role of RRM1 in predicting survival in patients with pancreatic cancer treated with gemcitabine. An extensive literature search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through May 1st, 2013. This meta-analysis was performed using the STATA 12.0 software and crude hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Eight clinical studies were included in this meta-analysis with a total of 665 pancreatic cancer patients treated with adjuvant gemcitabine-based chemotherapy, including 373 patients in the high RRM1 expression group and 292 patients in the low RRM1 expression group. Our meta-analysis revealed that high RRM1 expression was associated with improved overall survival (OS) of pancreatic cancer patients (HR=1.56, 95%CI=0.95-2.17, P<0.001). High RRM1 expression also was linked to longer disease-free survival (DFS) than low RRM1 expression (HR=1.37, 95%CI=0.25-2.48, P=0.016). In conclusion, our meta-analysis suggests that high RRM1 expression may be associated with improved OS and DFS of pancreatic cancer patients treated with adjuvant gemcitabine-based chemotherapy. Detection of RRM1 expression may be a promising biomarker for gemcitabine response and prognosis in pancreatic cancer patients.

Integration Sites and Genotype Distributions of Human Papillomavirus in Cervical Intraepithelial Neoplasia

Wang, Li,Dai, Shu-Zhen,Chu, Hui-Jun,Cui, Hong-Fei,Xu, Xiao-Yan Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.6

Objectives: To analyse HPV integration prevalence and genotype distributions in cervical intraepithelial neoplasia (CIN) in east part of China, furthermore to assess preferential sites for common HPV integrations and provide baseline information for cervical abnormality screening and prevention. Methods: Integration of HPV in 113 paraffin-embedded cervical intraepithelial neoplasia samples was assessed using Gencap technology in Key Laboratory of Biotechnologies in BGI-Shenzhen. Results: 64 samples were HPV-integrated and as the cervical lesions increased, the integration rate became higher significantly (P=0.002). Fifteen different HPV genotypes were detected, 14 high-risk (16, 18, 31, 33, 51, 52, 56, 58, 66, 68) and 1 low-risk (11). The most common genotypes were HPV-16, 58, 33, 52, 66, and 56. Thirteen patients had co-integration involving mainly HPV-16 and 58. The frequency of HPV gene disruption was higher in L1 and E1 genes than in other regions of the viral genomes. Conclusion: Some 56.6% of CIN lesions in Qingdao had HPV integrations, and 67.2% of HPV-integrated patients were HPV-16 and 58, more prone to be integrated in younger patients below 45 years old. There exist preferential sites for HPV-16 and HPV-58 integration, and they are more likely to be disrupted in the L1 and E1 loci.

Translationally controlled tumor protein (TCTP) downregulates Oct4 expression in mouse pluripotent cells

( Xiang Cheng ),( Jun Hua Li ),( Jie Deng ),( Zhen Zhen Li ),( Shu Yan Meng ),( Hua Yan Wang ) 생화학분자생물학회 2012 BMB Reports Vol.45 No.1

The present study aimed to investigate the function of translationally controlled tumor protein (TCTP) in the regulation of Oct4 in mouse embryonic carcinoma P19 cells and mouse J1 embryonic stem (ES) cells. The mRNA level of endogenous TCTP in somatic cells was 2-4 folds higher than that in pluripotent P19 and J1 ES cells. Overexpression of TCTP in mouse pluripotent cells not only reduced the level of Oct4 transcription, but also decreased the pluripotency of stem cells. The N-terminal end of TCTP (amino acids 1-60) played an important role in suppressing the Oct4 promoter. Moreover, overexpression of TCTP in P19 cells suppressed the Oct4 promoter activity in a dose- and a time-dependent manner. In addition, knockdown of TCTP by small interfering RNA increased the expression of Oct4. Our study indicates that TCTP downregulates the Oct4 expression by binding the Sf1 site of Oct4 promoter in mouse pluripotent cells. [BMB reports 2012; 45(1): 20-25]

Effects of Myogenin on Expression of Late Muscle Genes through MyoD-Dependent Chromatin Remodeling Ability of Myogenin

Chao Du,Ju-Hua Ni,Ya-Qiong Jin,Jun-Juan Qi,Zhen-Xing Ji,Shu-Yan Li,Guo-Shun An,Hong-Ti Jia 한국분자세포생물학회 2012 Molecules and cells Vol.34 No.2

MyoD and myogenin (Myog) recognize sets of distinct but overlapping target genes and play different roles in skeletal muscle differentiation. MyoD is sufficient for near-full expression of early targets, while Myog can only partially enhance expression of MyoD-initiated late muscle genes. However, the way in which Myog enhances the expression of MyoD-initiated late muscle genes remains unclear. Here, we examine the effects of Myog on chromatin remodeling at late muscle gene promoters and their activation within chromatin environment. Chromatin immunoprecipitation (ChIP) assay showed that Myog selectively bound to the regulatory sequences of late muscle genes. Overexpres-sion of Myog was found to overcome sodium butyrate-inhibited chromatin at late muscle genes in differ-entiating C2C12 myoblasts, shifting the transcriptional activation of these genes to an earlier time period. Furthermore, overexpression of Myog led to increased hyperacetylation of core histone H4 in differentiating C2C12 myoblasts but not NIH3T3 fibroblasts, and hyperacetylated H4 was associated directly with the late muscle genes in differentiating C2C12, indicating that Myog can induce chromatin remodeling in the presence of MyoD. In addition, co-immunopre-cipitation (CoIP) revealed that Myog was associated with the nuclear protein Brd4 in differentiating C2C12 myoblasts. Together, these results suggest that Myog enhances the expression of MyoD-initiated late muscle genes through MyoD-dependent ability of Myog to induce chromatin remodeling, in which Myog-Brd4 interaction may be involved.

Effects of Lactobacillus plantarum SCS2 on blood glucose level in hyperglycemia mice model

Xiao Meng,Yu Qian,Li-Shi Jiang,Jin-Mei Kang,Yan Chen,Juan Wang,Shu-Kun Liu,Zhen-Ming Che,Xin Zhao 한국응용생명화학회 2016 Applied Biological Chemistry (Appl Biol Chem) Vol.59 No.1

In this study, the hyperglycemia mice model was established with 1-week high sugar and fat diet plus with 70 mg/kg body weight of streptozotocin injection for 3 days. Sixty male Kunming mice of 3 weeks old in a specific-pathogen-free grade were divided into six groups randomly, which includes normal group (NG), prevention group (PG), treatment group for low dose (TGL), middle dose (TGM), high dose (TGH), and model group (MG). NG and MG mice were fed with sterile physiological saline (10 mL/kg body weight). PG mice were fed with the concentration of 6.0 × 109 CFU/mL L. plantarum SCS2 suspensions from the second to third week. TGL, TGM, and TGH mice were fed with the concentration of 2.0 × 109, 4.0 × 109, and 6.0 × 109 CFU/mL L. plantarum SCS2 suspensions (10 mL/kg body weight), respectively from fourth to tenth week. The results showed that the fasting and postprandial 2 h blood glucose levels of TGH mice were reduced by L. plantarum SCS2 significantly (p < 0.05) as compared with MG. The body weight of TGH mice came to normal level at tenth week. Content of K+ in plasma of TGH mice was increased and contents of Na+ and Cl− in the plasma of TGH mice were decreased as compared with MG. Meanwhile, content of glycogen in TGH mice was reduced. However, the effect of L. plantarum SCS2 on the prevention of hyperglycemia in PG mice was not significant as compared with NG mice during the experiment. These results suggested that L. plantarum SCS2 showed a hypoglycemic effect on hyperglycemic mice model.

Gentic overexpression increases production of hypocrellin A in Shiraia bambusicola S4201

Dan Li,Ning Zhao,Bing-Jing Guo,Xi Lin,Shuang-Lin Chen,Shu-Zhen Yan 한국미생물학회 2019 The journal of microbiology Vol.57 No.2

Hypocrellin A (HA) is a perylenequinone (PQ) isolated from Shiraia bambusicola that shows antiviral and antitumor activities, but its application is limited by the low production from wild fruiting body. A gene overexpressing method was expected to augment the production rate of HA in S. bambusicola. However, the application of this molecular biology technology in S. bambusicola was impeded by a low genetic transformation efficiency and little genomic information. To enhance the plasmid transformant ratio, the Polyethylene Glycol-mediated transformation system was established and optimized. The following green fluorescent protein (GFP) analysis showed that the gene fusion expression system we constructed with a GAPDH promoter Pgpd1 and a rapid 2A peptide was successfully expressed in the S. bambusicola S4201 strain. We successfully obtained the HA high-producing strains by overexpressing O-methyltransferase/FAD-dependent monooxygenase gene (mono) and the hydroxylase gene (hyd), which were the essential genes involved in our putative HA biosynthetic pathway. The overexpression of these two genes increased the production of HA by about 200% and 100%, respectively. In general, this study will provide a basis to identify the genes involved in the hypocrellin A biosynthesis. This improved transformation method can also be used in genetic transformation studies of other fungi.