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MiR-324-5p/PTPRD/CEBPD axis promotes papillary thyroid carcinoma progression via microenvironment alteration.

ABSTRACT: MiR-324-5p is overexpressed in papillary thyroid carcinoma (PTC) with lymph node metastasis and promotes malignant phenotypes of KTC-1 cell line. However, the detailed regulatory mechanism remains unknown. Tumor microenvironment plays a key role in tumor progression. CCAAT enhancer-binding protein delta (CEBPD) is important in immune and inflammatory responses. In this study, we investigated the interaction between miR-324-5p/PTPRD/CEBPD axis and tumor microenvironment in PTC progression. K1 and KTC-1 were transfected by lenti-CEBPD or CEBPD-sh vectors. Supernatant from different groups was harvested and added into culture media of human macrophages and HUVEC. Cell viability, colony formation, invasive and migrated cell number, and gap closure rate were elevated in lenti-CEBPD group. Compared with the control, supernatant from lenti-CEBPD group contained more abundant levels of VEGF and IL-4/IL-13, which, respectively, induced higher HUVEC invasion/migration rates and more obvious M2 marker (CD206) and genes (PPAR-γ and MRC-1) expression in macrophages. By means of luciferase reporter assay and gene manipulation, we identified that CEBPD was negatively regulated in PTC by protein tyrosine phosphatase receptor delta (PTPRD) which was the target of miR-324-5p. CEBPD-shRNA was also proved to reverse the effect of PTPRD-sh1 or miR-324-5p mimic on IL-4/IL-13 expression and HUVEC invasion. These results suggested that miR-324-5p/PTPRD/CEBPD axis was involved in the progression of PTC by inducing HUVEC invasion/migration and macrophage M2 polarization via VEGF and IL4/IL13, respectively.

SUBMITTER: Yang Y

PROVIDER: S-EPMC7515492 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Papillary thyroid carcinoma (PTC) is the most common endocrine cancer with a significantly increase of the incidence recently. Several cytokines, such as thyroid peroxidase (TPO), cluster of differentiation 56 (CD56), Galectin-3, mesothelial cell (MC), cytokeratin 19 (CK19) and BRAF (B-raf) were recommended to be tested by immunohistochemistry (IHC) for a definitive diagnosis, but were still limited in clinical use because of their relative lower sensitivity and specificity. MicroRNA (miRNA), as a new molecular biomarkers, however, has not been reported yet so far. To address this, hsa-miR-200a-5p, a miRNA, was selected and detected in PTC patients by in situ hybrization with benign thyroid tumor with papillary hyperplasia as a control, and the differential expression of hsa-miR-200a-5p between fresh PTC tissues and control was detected by qRT-PCR. Expressive levels of cytokines of TPO, CD56, Galectin-3, MC, CK19 and B-raf were also detected by immunohistochemistry. The correlation was analyzed by SPSS software using Spearman methods. As expected, the hsa-miR-200a-5p expressive level was significantly increased in PTC patients, compared to that of control, and was consistent with that of TPO, CD56, Galectin-3, MC, CK19 and B-raf. In addition, expression of hsa-miR-200a-5p showed negative correlation to that of TPO (rs = - 0.734; **: P < 0.01) and CD56 (rs = - 0.570; **: P < 0.01), but positive correlation to that of Galectin-3 (rs = 0.601; **: P < 0.01), MC (rs = 0.508; **: P < 0.01), CK19 (rs = 0.712; **: P < 0.01) and B-raf (rs = 0.378; **: P < 0.01). PTC and papillary benign thyroid papillary hyperplasia are difficult to distinguish in morphology, so requiring immunohistochemistry to further differentiate the diagnosis, however, for the existing clinical common diagnostic marker for immunohistochemistry, the sensitivity and accuracy are low, it is easy to miss diagnosis. Therefore, there is an urgent need for a rapid and sensitive molecular marker. So miR-200a-5p can be used to assist in the diagnosis of PTC at the molecular level, and as a biomarker, can be effectively used to distinguish between PTC and benign thyroid tumor with papillary hyperplasia.

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MiR-324-5p/PTPRD/CEBPD axis promotes papillary thyroid carcinoma progression via microenvironment alteration.

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