NOVA1 inhibition by miR-146b-5p in the remnant tissue microenvironment defines occult residual disease after gastric cancer removal
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Sun Och Yoon1,*, Eun Kyung Kim1,*, Mira Lee1, Woon Yong Jung2, Hyunjoo Lee3, Youngran Kang2, You-Jin Jang4, Soon Won Hong1, Seung Ho Choi5, and Woo Ick Yang1
1Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
2Department of Pathology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
3Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul, Korea
4Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
5Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
*These authors have contributed equally to this work
Keywords: microenvironment, residual disease, hsa-microRNA-146b-5p, NOVA1, stromal cells
Received: July 14, 2015 Accepted: November 21, 2015 Published: December 09, 2015
Occult residual disease in remnant tissues could be the cause of tumor relapse. To identify signal molecules and target cells that may be indicative of occult residual disease within a remnant microenvironment, proximal resection margin tissues of gastric cancers were used, as these correspond to the nearest remnant tissues after gastrectomy. Increased miR-146b-5p in the remnant microenvironment was determined to be a strong risk factor for tumor relapse and poor survival rate. NOVA1, a target gene of miR-146b-5p, was decreased in remnant tissues of patients with a poor prognosis. NOVA1 was enriched in stromal spindle cells such as fibroblasts within normal tissues. In non-neoplastic inflammation, such as gastritis, NOVA1 was highly enriched in T lymphocytes and stromal spindle cells, while expression of this protein was frequently decreased in those types of cells within gastric cancer tissues. Particularly, decreased NOVA1 in T cells within the gastric cancer tissues was correlated with decreased FOXP3-positive regulatory T cells and was associated with poor patient prognosis. In vitro analysis showed that the NOVA1 gene was inhibited by miR-146b-5p. In immune cells as well as stromal spindle cells, decreased NOVA1, possibly inhibited by miR-146b-5p, is a candidate biomarker predicting poor prognosis of gastric cancer patients and is also a biomarker of occult residual disease in remnant tissues after gastric cancer removal.
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