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// Xiongyan Wu 1, * , Pan Tao 1, * , Quan Zhou 1, * , Jie Li 1 , Zhenjia Yu 1 , Xiaofeng Wang 1 , Jiaanfang Li 1 , Chen Li 1 , Min Yan 1 , Zhenggang Zhu 1 , Bingya Liu 1 , Liping Su 1 1 Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, People’s Republic of China * These authors contributed equally to this work Correspondence to: Liping Su, email: suliping@shsmu.edu.cn Keywords: cancer-associated fibroblasts, interleukin-6, JAK/STAT3, gastric cancer Received: July 22, 2016 Accepted: January 23, 2017 Published: February 06, 2017 ABSTRACT Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. However, the molecular mechanisms underlying the tumor-promoting properties of CAFs in gastric cancer remain unclear. Here, we show that CAFs isolated from gastric cancer produce significant amounts of interleukin-6 (IL-6). CAFs enhances the migration and EMT of gastric cancer cells through the secretion of IL-6 that activates Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT3) pathway in gastric cancer cells, while deprivation of IL-6 using a neutralizing antibody or inhibition of JAK/STAT3 pathway with specific inhibitor AG490 markedly attenuates these phenotypes in gastric cancer cells induced by CAFs. Moreover, silencing IL-6 expression in CAFs or inhibiting JAK2/STAT3 pathway in gastric cancer cells impairs tumor peritoneal metastasis induced by CAFs in vivo . Taken together, these results suggest that CAFs in the tumor microenvironment promote the progression of gastric cancer through IL-6/JAK2/STAT3 signaling, and IL-6 targeted therapy could be a complementary approach against gastric cancer by exerting their action on stromal fibroblasts.

// Chenchen Wang 1, * , Quan Zhou 1, * , Xiaofeng Wang 1 , Xiongyan Wu 1 , Xuehua Chen 1 , Jianfang Li 1 , Zhenggang Zhu 1 , Bingya Liu 1 , Liping Su 1 1 Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Liping Su, e-mail: franesulp@hotmail.com Bingya Liu, e-mail: byliu@sjtu.edu.cn Keywords: TLR7, Treg cells, Immune suppression, Anti-tumor effect Received: October 08, 2014 Accepted: November 16, 2014 Published: December 15, 2014 ABSTRACT Treg-induced immunosuppression is now recognized as a key element in enabling tumors to escape immune-mediated destruction. Although topical TLR7 therapies such as imiquimod have been proved successful in the treatment of dermatological malignancy and a number of conditions beyond the FDA-approved indications, the mechanism behind the effect of TLR7 on effector T cell and Treg cell function in cancer immunosurveillance is still not well understood. Here, we found that Loxoribin, one of the TLR7 ligands, could inhibit tumor growth in xenograft models of colon cancer and lung cancer, and these anti-tumor effects of Loxoribin were mediated by promoting CD4 + T cell proliferation and reversing Treg-mediated suppression via dendritic cells (DCs). However, deprivation of IL-6 using a neutralizing antibody abrogated the ability of Loxoribin-treated DCs, which reversed the Treg cell-mediated suppression. Furthermore, adoptive transfer of Loxoribin-treated DCs inhibited the tumor growth in vivo . Thus, this study links TLR7 signaling to the functional control of effector T cells and Treg cells and identifies Loxoribin as a new therapeutic strategy in cancer treatment, which may offer new opportunities to improve the outcome of cancer immunotherapy.

// Yao-fei Pei 1, * , Ran Tao 2, * , Jian-fang Li 1 , Li-ping Su 1 , Bei-qin Yu 1 , Xiong-yan Wu 1 , Min Yan 1 , Qin-long Gu 1 , Zheng-gang Zhu 1 , Bing-ya Liu 1 1 Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China 2 Department of Hepatobiliary-Pancreatic Surgery, Zhejiang Province People’s Hospital, Hangzhou 310014, PR China * These authors have contributed equally to this work Correspondence to: Bing-ya Liu, email: liubingya@sjtu.edu.cn Keywords: TET1, 5-methylcytosine, 5-hydroxymethylcytosine, gastric cancer, PTEN Received: February 17, 2016 Accepted: March 31, 2016 Published: April 21, 2016 ABSTRACT Ten-Eleven Translocation 1 (TET1) is a member of ten eleven translocation enzymes, which convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). TET1 can promote CpG islands demethylation in specific genes and often absent in various cancers. Herein, we found that TET1 expression and 5-hmC content were low in gastric tumors compared to its adjacent non-tumor tissues. Cell proliferation, migration and invasion were enhanced upon TET1 knockdown in gastric cancer cells in vitro . This phenomenon was confirmed by an animal xeongraft model. We also found that TET1 directly binds to the promoter region of PTEN and activates its transcription through demethylation of CpG islands. TET1 knockdown activated AKT and FAK pathways, which were suppressed by PTEN. The activation of AKT and FAK facilitated tumor migration, invasion and accelerated cell growth. In conclusion, we found a novel mechanism that TET1 suppresses tumor cell growth, migration and invasion through demethylation of CpG island in PTEN promoter by increasing 5-hmC content. The re-expressed PTEN subsequently down regulates AKT and FAK activity.

// Xiaofeng Wang 1,* , Zhenjia Yu 1,* , Quan Zhou 1 , Xiongyan Wu 1 , Xuehua Chen 1 , Jianfang Li 1 , Zhenggang Zhu 1 , Bingya Liu 1 and Liping Su 1 1 Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Liping Su, email: // Keywords : TG2, gastric cancer, ERK1/2, tumor progression Received : August 26, 2015 Accepted : January 04, 2016 Published : January 11, 2016 Abstract Gastric cancer (GC) is one of the most common tumors worldwide and involves extensive local tumor invasion, metastasis, and poor prognosis. Understanding mechanisms regulating progression of GC is necessary for developing effective therapeutic strategies. Tissue transglutaminase-2 (TG2), a multifunctional member of the transglutaminase family, has been shown to be critical for tumor initiation and progression. However, how TG2 promotes the progression of GC is unknown. We report that TG2 was highly expressed in GC tissues and positively associated with depth of tumor invasion and late TNM stage. With gain- and loss-of-function approaches, we observed that TG2 promoted GC cell proliferation, migration, invasion, as well as tumorigenesis and peritoneal metastasis in vivo . These events were associated with the ERK1/2 pathway activation and an ERK1/2 inhibitor (U0126) inhibited cell proliferation, migration, and invasion induced by overexpression of TG2. In summary, TG2 contributes to tumorigenesis and progression of GC by activating the ERK1/2 signaling pathway and is a potential therapeutic target of metastatic gastric cancer.