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Am J Cancer Res. 2017 Sep 1;7(9):1913-1925. eCollection 2017.

Tumor microenvironment interruption: a novel anti-cancer mechanism of Proton-pump inhibitor in gastric cancer by suppressing the release of microRNA-carrying exosomes.

Guan XW1,2, Zhao F1,2, Wang JY1,2, Wang HY3, Ge SH1,2, Wang X1,2, Zhang L1,2, Liu R1,2, Ba Y1,2, Li HL1,2, Deng T1,2, Zhou LK1,2, Bai M1,2, Ning T1,2, Zhang HY1,2, Huang DZ1,2.

Author information

1
Department of Gastrointestinal Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for CancerTianjin, China.
2
Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for CancerTianjin, China.
3
Department of Radiotherapy, Cangzhou Central HospitalHebei, China.

Abstract

Poor prognosis of gastric cancer is related to not only malignancy of gastric cancer cells, but also the tumor microenvironment. Thus drugs, which can inhibit both of them, are urgently needed to be explored. Studies on effect of Proton-pump inhibitors (PPIs) in anti-neoplasms are increasing, but is rare in gastric in gastric cancer. Here we investigated how the gastric cancer microenvironment is regulated by PPIs. The objective response rate of gastric cancer patients in our hospital treated by PPIs is investigated. PPIs' effects were further explored by observing the change of microRNAs, cytokines, cellular apoptosis. Bioinformatic pathway analysis of microarray was used to discover the pathway involved in PPIs' regulation of gastric cancer microenvironments. Immunoblotting assays and qRT-PCR were used to define molecular events with PPIs treatment. We report here that PPIs can improve the prognosis of advanced gastric cancer patients; and inhibit the progress of gastric cancer both in vivo and in vitro. Moreover, high dose of PPIs can regulate the pathway associated with tumor malignancy and microenvironment via inhibiting the release of exosomes, which packed microRNAs. PPIs can inhibit the transformation of CAFs (cancer associated fibroblasts) and cytokines released from CAFs. In addition, PPIs inhibit the malignancy of gastric cancer through regulating HIF-1α-FOXO1 axis. High dose of PPIs can inhibit malignancy of gastric cancer and regulate its surrounding tumor microenvironment. This finding suggests that PPIs maybe of potential value as a therapeutic tool for treatment of gastric cancer.

KEYWORDS:

Proton-pump inhibitor; exosome; gastric cancer; microRNA

PMID:
28979813
PMCID:
PMC5622225

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