MicroRNA-335-5p is a potential suppressor of metastasis and invasion in gastric cancer
Authors: Gonzalo Carrasco-Avino
Lorena Lobos-González
Gareth I Owen
Nicolás Carrasco-Véliz
Ismael Riquelme
Enrique Norero
Alejandra Sandoval-Bórquez
Iva Polakovicova
Alejandro H Corvalán
Juan C Roa
Carolina Bizama
Journal: Clinical Epigenetics (2017)
Discipline: CLINICAL MEDICINE
Keywords: CDH11; Gastric cancer; Metastasis; Methylation; PLAUR
Affiliations: Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Santiago, Chile., Laboratory of Molecular Pathology, Department of Pathology, School of Medicine, BIOREN-CEGIN, and Graduate Program in Applied Cell and Molecular Biology, Universidad de La Frontera, Temuco, Chile., Center UC for Investigational in Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile., Instituto de Química, Faculty of Science, Pontificia Universidad Católica de Valparaíso, Valparaiso, Chile., Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago, Chile., Fundación Ciencia y Vida, Parque Biotecnológico, Santiago, Chile., Department of Pathology, Faculty of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile., Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile., Esophagogastric Surgery Unit, Hospital Dr. Sótero del Río, Santiago, Chile., Digestive Surgery Department, Pontificia Universidad Católica de Chile, Santiago, Chile., Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile., Department of Hematology-Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Abstract:  Background: Multiple aberrant microRNA expression has been reported in gastric cancer. Among them, microRNA-335-5p (miR-335), a microRNA regulated by DNA methylation, has been reported to possess both tumor suppressor and tumor promoter activities. Results: Herein, we show that miR-335 levels are reduced in gastric cancer and significantly associate with lymph node metastasis, depth of tumor invasion, and ultimately poor patient survival in a cohort of Amerindian/Hispanic patients. In two gastric cancer cell lines AGS and, Hs 746T the exogenous miR-335 decreases migration, invasion, viability, and anchorage-independent cell growth capacities. Performing a PCR array on cells transfected with miR-335, 19 (30.6%) out of 62 genes involved in metastasis and tumor invasion showed decreased transcription levels. Network enrichment analysis narrowed these genes to nine (PLAUR, CDH11, COL4A2, CTGF, CTSK, MMP7, PDGFA, TIMP1, and TIMP2). Elevated levels of PLAUR, a validated target gene, and CDH11 were confirmed in tumors with low expression of miR-335. The 3'UTR of CDH11 was identified to be directly targeted by miR-335. Downregulation of miR-335 was also demonstrated in plasma samples from gastric cancer patients and inversely correlated with DNA methylation of promoter region (Z = 1.96, p = 0.029). DNA methylation, evaluated by methylation-specific PCR assay, was found in plasma from 23 (56.1%) out of 41 gastric cancer patients but in only 9 (30%) out of 30 healthy donors (p = 0.029, Pearson's correlation). Taken in consideration, our results of the association with depth of invasion, lymph node metastasis, and poor prognosis together with functional assays on cell migration, invasion, and tumorigenicity are in accordance with the downregulation of miR-335 in gastric cancer. Conclusions: Comprehensive evaluation of metastasis and invasion pathway identified a subset of associated genes and confirmed PLAUR and CDH11, both targets of miR-335, to be overexpressed in gastric cancer tissues. DNA methylation of miR-335 may be a promissory strategy for non-invasive approach to gastric cancer. 

Retracted: No

PubPeer comments:
 Figure 2A appears to have 2 images which overlap. *** ![file] , 
 There was an error in the edition of these images, however the results presented in the publication are true. The authors apologize for inconvenience. , 
 #2 Are the authors intending to publish a correction? , 
 #3 Yes, the correction is published now. Sandovalu2011Bu00f3rquez et al. Clin Epigenet (2021) Mar 8;13(1):50. https: doi.org 10.1186 s13148u2011021u201101036u20112 , 
 Following publication of the original article [1], the authors (sic) identified an error in Fig. 2. The correct figure is given below (Fig. 2). ![file] ,