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>

Efficacy of Prophylactic Entecavir for Hepatitis B Virus-Related Hepatocellular Carcinoma Receiving Transcatheter Arterial Chemoembolization

Li, Xing,Zhong, Xiang,Chen, Zhan-Hong,Wang, Tian-Tian,Ma, Xiao-Kun,Xing, Yan-Fang,Wu, Dong-Hao,Dong, Min,Chen, Jie,Ruan, Dan-Yun,Lin, Ze-Xiao,Wen, Jing-Yun,Wei, Li,Wu, Xiang-Yuan,Lin, Qu Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.18

Background and Aims: Hepatitis B virus (HBV) reactivation was reported to be induced by transcatheter arterial chemoembolization (TACE) in HBV-related hepatocellular carcinonma (HCC) patients with a high incidence. The effective strategy to reduce hepatitis flares due to HBV reactivation in this specific group of patients was limited to lamivudine. This retrospective study was aimed to investigate the efficacy of prophylactic entecavir in HCC patients receiving TACE. Methods: A consecutive series of 191 HBV-related HCC patients receiving TACE were analyzed including 44 patients received prophylactic entecavir. Virologic events, defined as an increase in serum HBV DNA level to more than 1 log10 copies/ml higher than nadir the level, and hepatitis flares due to HBV reactivation were the main endpoints. Results: Patients with or without prophylactic were similar in host factors and the majorities of characteristics regarding to tumor factors, HBV status, liver function and LMR. Notably, cycles of TACE were parallel between the groups. Ten (22.7%) patients receiving prophylactic entecavir reached virologic response. The patients receiving prophylactic entecavir presented significantly reduced virologic events (6.8% vs 54.4%, p=0.000) and hepatitis flares due to HBV reactivation (0.0% vs 11.6%, p=0.039) compared with patients without prophylaxis. Kaplan-Meier analysis illustrated that the patients in the entecavir group presented significantly improved virologic events free survival (p=0.000) and hepatitis flare free survival (p=0.017). Female and Eastern Cooperative Oncology Group (ECOG) performance status 2 was the only significant predictors for virological events in patients without prophylactic antiviral. Rescue antiviral therapy did not reduce the incidence of hepatitis flares due to HBV reactivation. Conclusion: Prophylactic entecavir presented promising efficacy in HBV-related cancer patients receiving TACE. Lower performance status and female gender might be the predictors for HBV reactivation in these patients.

Neutrophil Count and the Inflammation-based Glasgow Prognostic Score Predict Survival in Patients with Advanced Gastric Cancer Receiving First-line Chemotherapy

Li, Qing-Qing,Lu, Zhi-Hao,Yang, Li,Lu, Ming,Zhang, Xiao-Tian,Li, Jian,Zhou, Jun,Wang, Xi-Cheng,Gong, Ji-Fang,Gao, Jing,Li, Jie,Li, Yan,Shen, Lin Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.2

Purpose: To explore the value of systemic inflammatory markers as independent prognostic factors and the extent these markers improve prognostic classification for patients with inoperable advanced or metastatic gastric cancer (GC) receiving palliative chemotherapy. Methods: We studied the prognostic value of systemic inflammatory factors such as circulating white blood cell count and its components as well as that combined to form inflammation-based prognostic scores (Glasgow Prognostic Score (GPS), Neutrophil-Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Prognostic Index (PI) and Prognostic Nutritional Index (PNI)) in 384 patients with inoperable advanced or metastatic gastric cancer (GC) receiving first-line chemotherapy. Univariate and multivariate analyses were performed to examine the impact of inflammatory markers on overall survival (OS). Results: Univariate analysis revealed that an elevated white blood cell, neutrophil and/or platelet count, a decreased lymphocyte count, a low serum albumin concentration, and high CRP concentration, as well as elevated NLR/PLR, GPS, PI, PNI were significant predictors of shorter OS. Multivariate analysis demonstrated that only elevated neutrophil count (HR 3.696, p=0.003) and higher GPS (HR 1.621, p=0.01) were independent predictors of poor OS. Conclusion: This study demonstrated elevated pretreatment neutrophil count and high GPS to be independent predictors of shorter OS in inoperable advanced or metastatic GC patients treated with first-line chemotherapy. Upon validation of these data in independent studies, stratification of patients using these markers in future clinical trials is recommended.

Association Between MDM2 SNP309 T>G and Risk of Gastric Cancer: A Meta-analysis

Tian, Xin,Tian, Ye,Ma, Ping,Sui, Cheng-Guang,Meng, Fan-Dong,Li, Yan,Fu, Li-Ye,Jiang, Tao,Wang, Yang,Ji, Fu-Jian,Fang, Xue-Dong,Jiang, You-Hong Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.3

Background: As a negative regulator of P53, MDM2 plays an important role in carcinogenesis; a polymorphism in its promoter region. SNP309 T>G, is known to increase the expression of MDM2, thus being considered related to higher susceptibility to neoplasia. However, no agreement has been achieved regarding its effects on gastric cancer. Methods: The present systematic meta-analysis was performed based on comprehensive literature search from Pubmed, Web of science and CBM databases. Results: It was suggested from 6 independent studies that the GG genotype is associated with a significantly increased risk of gastric cancer (Recessive: OR = 1.43, 95% CI = 1.08-1.91, P = 0.013), and subgroup analysis also confirmed the relationship (English publications-recessive model: OR = 1.45, 95% CI = 1.10-1.91, P = 0.009; Studies in China-recessive model: OR = 1.58, 95% CI = 1.08-2.30, P = 0.017). No publication bias was detected. Conclusion: The meta-analysis indicated a significant inverse association between GG genotype carriage and elevated risk of gastric cancer. However, more studies and detailed information are needed to fully address the topic.

Staged Improvement in Awareness of Disease for Elderly Cancer Patients in Southern China

Li, Xing,Dong, Min,Wen, Jing-Yun,Wei, Li,Ma, Xiao-Kun,Xing, Yan-Fang,Deng, Yun,Chen, Zhan-Hong,Chen, Jie,Ruan, Dan-Yun,Lin, Ze-Xiao,Wang, Tian-Tian,Wu, Dong-Hao,Liu, Xu,Hu, Hai-Tao,Lin, Jia-Yu,Li, Zhu Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.15

Background: In mainland China, awareness of disease of elderly cancer patients largely relies on the patients' families. We developed a staged procedure to improve their awareness of disease. Materials and Methods: Participants were 224 elderly cancer patients from 9 leading hospitals across Southern China. A questionnaire was given to the oncologists in charge of each patient to evaluate the interaction between family and patients, patient awareness of their disease and participation in medical decision-making. After first cycles of treatment, increased information of disease was given to patients with cooperation of the family. Then patient awareness of their disease and participation in medical decision-making was documented. Results: Among the 224 cancer elderly patients, 26 (11.6%) made decisions by themselves and 125 (55.8%) delegated their rights of decision-making to their family. Subordinate family members tended to play a passive role in decision-making significantly. Patients participating more in medical decision-making tended to know more about their disease. However, in contrast to the awareness of disease, patient awareness of violation of medical recommendations was reversely associated with their participation in medical decision-making. Improvement in awareness of diagnosis, stages and prognosis was achieved in about 20% elderly cancer patients. About 5% participated more actively in medical decision-making. Conclusions: Chinese elderly cancer patient awareness of disease and participation in medical decision-making is limited and relies on their family status. The staged procedure we developed to improve patient awareness of disease proved effective.

Two New Metabolites with Cytotoxicities from Deep-Sea Fungus, Aspergillus sydowi YH11-2

Li, De-Hai,Cai, Sheng-Xin,Tian, Li,Lin, Zhen-Jian,Zhu, Tian-Jiao,Fang, Yu-Chun,Liu, Pei-Pei,Zhu, Wei-Ming,Gu, Qian-Qun 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.9

Two new compounds, 2, 3, 5-trimethyl-6-(3-oxobutan-2-yl)-4H-pyran-4-one (1) and (2R)-2, 3-dihydro-7-hydroxy-6, 8-dimethyl-2-[(E)-prop-1-enyl] chromen-4-one (2), together with six known compounds (3-8), were isolated from a deep-sea fungus, identified as Aspergillus sydowi, by a bioassay-guided method. Their structures were elucidated by spectroscopic methods and the cytotoxicities were evaluated by SRB method.

Significance of Thrombocytosis in Clinicopathologic Characteristics and Prognosis of Gastric Cancer

Li, Fang-Xuan,Wei, Li-Juan,Zhang, Huan,Li, Shi-Xia,Liu, Jun-Tian Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.16

Purpose: We aimed to study the relationship between thrombocytosis and clinical features of gastric cancerfocussing on platelet counts and gastric cancer progression through different TNM stages. Methods: According to the normal range of platelet count in our institution, 1,596 patients were divided to two groups: a thrombocytosis group (120 patients, > $400{\times}1000/{\mu}L$) and a control group (1,476 patients, ${\leq}400{\times}1000/{\mu}L$). Results: The incidence of thrombocytosis was 7.5%. Higher platelet counts were observed in patients with older age, larger tumor size, deeper invasion, lymph node metastasis, distant metastasis and advanced TNM stage. In multivariate logistic regression, tumor size, depth of tumor invasion, lymph node metastasis and TNM stage were independent risk factors for thrombocytosis of gastric cancer patients. On prognostic analysis, age, tumor size, tumor location, histologic type, depth of tumor invasion, lymph node metastasis, distant metastasis and TNM stage and platelet count were important factors. Tumor size, invasion depth, lymph node metastasis, TNM stage and the platelet count were independent prognostic factors. Conclusion: Thrombocytosis is associated with clinical features of gastric cancer patients and correlates with a poor prognosis.

Hepatitis B Virus DNA Negativity Acts as a Favorable Prognostic Factor in Hepatocellular Carcinoma Patients

Li, Xing,Zhong, Xiang,Chen, Zhan-Hong,Xing, Yan-Fang,Wu, Dong-Hao,Chen, Jie,Ma, Xiao-Kun,Lin, Qu,Wen, Jing-Yun,Wei, Li,Wang, Tian-Tian,Ruan, Dan-Yun,Lin, Ze-Xiao,Wu, Xiang-Yuan,Dong, Min Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.22

Background: This retrospective study was aimed to investigate the efficacy of prophylactic agents in hepatocellular carcinoma (HCC) patients receiving TACE and compare the difference between lamivudine and entecavir. Materials and Methods: A consecutive series of 203 HBV-related HCC patients receiving TACE were analyzed including 91 patients given prophylactic agents. Virologic events, defined as an increase in serum HBV DNA level to more than 1 log10 IU/ml higher than the nadir level, hepatitis flares due to HBV reactivation and progression free survival (PFS) were the main endpoints. Results: Some 48 (69.6%) reached virologic response. Prophylaxis significantly reduced virologic events (8.8% vs 58.0%, p=0.000) and hepatitis flares (1.1% vs 13.4%, p=0.001). Patients presenting undetectable HBV DNA levels displayed a significantly improved PFS as compared to those who never achieved undetectable HBV DNA. Prophylaxis and e-antigen positivity were the only significant variables associated with virologic events. In addition, prophylaxis was the only independent protective factor for hepatitis flares. Liver cirrhosis, more cycles of TACE, HBV DNA negativity, a lower Cancer of the Liver Italian Program score, non-metastasis and no hepatitis flares were protective factors for PFS. Prophylactic lamivudine demonstrated similar efficacy as entecavir. Conclusions: Prophylactic agents are efficacious for prevention of HBV reactivation in HCC patients receiving TACE. Achievement of undetectable HBV DNA levels displayed a significant capability in improving PFS. Moreover, persistent tumor residual lesions, positive HBV DNA and hepatitis B flares might be causes of tumor progression in these patients.

Gene cloning and functional analysis of yellow green leaf 3 (ygl3) gene during the whole-plant growth stage in rice

Xiaoqing Tian,Ying-Hua Ling,Li-kui Fang,Peng Du,Xian-Chun Sang,Fang-Ming Zhao,Yun-Feng Li,Rong Xie,Guang-Hua He 한국유전학회 2013 Genes & Genomics Vol.35 No.1

Chlorophyll is an important photosynthetic pigment in the process of photosynthesis in plants and photosynthetic bacteria. Genes involved in chlorophyll biosynthesis in Arabidopsis and photosynthetic bacteria have been well documented. In rice, however, these genes have not been fully annotated. In this paper, a yellow-green leaf gene, yellow green leaf3 (ygl3) was cloned and analyzed. ygl3 encodes magnesium chelation ChlD (D) subunit,a key enzyme for chlorophyll synthesis, resulting in a yellow-green leaf phenotype in all growth stages in rice. Expression content of ygl3 is highest in the leaf blades,followed by the leaf sheaths, while there is virtually no expression of the gene in the stems and seeds. The subcellular structure and protein content of the photosynthetic system of the ygl3 mutant were revealed by transmission electron microscopy, BN-PAGE, and western blotting. The results show that the mutation of the ygl3 gene indirectly leads to a decrease in the protein content of the photosynthetic system and severely obstructs the formation of granum thylakoids.

PKM2 Regulates Hepatocellular Carcinoma Cell Epithelial-mesenchymal Transition and Migration upon EGFR Activation

Fan, Fang-Tian,Shen, Cun-Si,Tao, Li,Tian, Chao,Liu, Zhao-Guo,Zhu, Zhi-Jie,Liu, Yu-Ping,Pei, Chang-Song,Wu, Hong-Yan,Zhang, Lei,Wang, Ai-Yun,Zheng, Shi-Zhong,Huang, Shi-Le,Lu, Yin Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.5

Pyruvate kinase isozyme type M2 (PKM2) was first found in hepatocellular carcinoma (HCC), and its expression has been thought to correlate with prognosis. A large number of studies have demonstrated that epithelial-mesenchymal transition (EMT) is a crucial event in hepatocellular carcinoma (HCC) and associated metastasis, resulting in enhanced malignancy of HCC. However, the roles of PKM2 in HCC EMT and metastasis remain largely unknown. The present study aimed to determine the effects of PKM2 in EGF-induced HCC EMT and elucidate the molecular mechanisms in vitro. Our results showed that EGF promoted EMT in HCC cell lines as evidenced by altered morphology, expression of EMT-associated markers, and enhanced invasion capacity. Furthermore, the present study also revealed that nuclear translocation of PKM2, which is regulated by the ERK pathway, regulated ${\beta}$-catenin-TCF/LEF-1 transcriptional activity and associated EMT in HCC cell lines. These discoveries provide evidence of novel roles of PKM2 in the progression of HCC and potential therapeutic target for advanced cases.