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// Huihui Chen 1, * , Wei Lu 1, 3, * , Chongjie Huang 2, * , Kefeng Ding 1 , Dajing Xia 3 , Yihua Wu 3, 4 and Mao Cai 2 1 Department of Oncology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China 2 Department of Anorectal Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China 3 Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, China 4 Department of Epidemiology and Health Statistics, Zhejiang University School of Public Health, Hangzhou, China * These authors have considered co-first authors Correspondence to: Mao Cai, email: caicai20012001@sina.com Yihua Wu, email: georgewuer@126.com Keywords: ZEB family, digestive cancer, prognostic value, cohort-based analysis, secondary analysis Received: October 02, 2016 Accepted: November 24, 2016 Published: February 23, 2017 ABSTRACT Background: Digestive cancers are common malignancies worldwide, however there are few effective prognostic markers available. In this study we comprehensively investigated the prognostic significance of ZEB1 and ZEB2 in digestive cancers. Methods: Electronic databases were searched and studies met the selection criteria were included. Study information was recorded and quality assessment was performed according to the REMARK guideline. Hazard ratios and its corresponding 95% confidence intervals were extracted and pooled. Sensitivity analyses, subgroup analyses, cumulative meta-analyses and secondary analyses were also performed to increase the stability and reliability of our results. Results: 24 cohort studies were included in the study. High ZEB1 and ZEB2 levels predicted poor overall survival, meanwhile high ZEB2 levels predicted poor disease free survival for digestive cancer patients. From subgroup analyses we observed ZEB1 was found to be significantly associated with poor overall survival for patients with pancreatic cancer, gastric cancer and colorectal cancer, while ZEB2 was found to be significantly associated with poor overall survival for patients with hepatocellular carcinoma and gastric cancer. Furthermore, by conducting secondary analyses we confirmed both ZEB1 and ZEB2 played important roles in gastric cancer prediction. In addition, we found high ZEB1 and ZEB2 expression were significantly associated with depth of invasion, lymph node metastasis and TNM stage in digestive cancer patients. Conclusions: The present study validated the prognostic value and clinicopathological association of ZEB1 and ZEB2 in digestive cancers, especially in gastric cancer.

Accumulated evidence suggests that M2-like polarized tumor associated macrophages (TAMs) plays an important role in cancer progression and metastasis, establishing TAMs, especially M2-like TAMs as an appealing target for therapy intervention. Here we found that metformin significantly suppressed IL-13 induced M2-like polarization of macrophages, as illustrated by reduced expression of CD206, down-regulation of M2 marker mRNAs, and inhibition of M2-like macrophages promoted migration of cancer cells and endothelial cells. Metformin triggered AMPKα1 activation in macrophage and silencing of AMPKα1 partially abrogated the inhibitory effect of metformin in IL-13 induced M2-like polarization. Administration of AICAR, another activator of AMPK, also blocked the M2-like polarization of macrophages. Metformin greatly reduced the number of metastases of Lewis lung cancer without affecting tumor growth. In tumor tissues, the percentage of M2-like macrophage was decreased and the area of pericyte-coated vessels was increased. Further, the anti-metastatic effect of metformin was abolished when the animals were treated with macrophages eliminating agent clodronate liposome. These findings suggest that metformin is able to block the M2-like polarization of macrophages partially through AMPKα1, which plays an important role in metformin inhibited metastasis of Lewis lung cancer.