Circulating microRNAs from the miR-106a–363 cluster on chromosome X as novel diagnostic biomarkers for breast cancer

Abstract

PurposeNovel noninvasive biomarkers with high sensitivity and specificity for the diagnosis of breast cancer (BC) are urgently needed in clinics. The aim of this study was to explore whether miRNAs from the miR-106a–363 cluster can be detected in the circulation of BC patients and whether these miRNAs can serve as potential diagnostic biomarkers.MethodsThe expression of 12 miRNAs from the miR-106a–363 cluster was evaluated using qRT-PCR in 400 plasma samples (from 200 BC patients and 200 healthy controls (HCs)) and 406 serum samples (from 204 BC patients and 202 HCs) via a three-phase study. The identified miRNAs were further examined in tissues (32 paired breast tissues), plasma exosomes (from 32 BC patients and 32 HCs), and serum exosomes (from 32 BC patients and 32 HCs).ResultsUpregulated levels of four plasma miRNAs (miR-106a-3p, miR-106a-5p, miR-20b-5p, and miR-92a-2-5p) and four serum miRNAs (miR-106a-5p, miR-19b-3p, miR-20b-5p, and miR-92a-3p) were identified and validated in BC. A plasma 4-miRNA panel and a serum 4-miRNA panel were constructed to discriminate BC patients from HCs. The areas under the receiver-operating characteristic curves of the plasma panel were 0.880, 0.902, and 0.858, and those of the serum panel were 0.910, 0.974, and 0.949 for the training, testing, and external validation phases, respectively. Two overlapping miRNAs (miR-106a-5p and miR-20b-5p) were consistently upregulated in BC tissues. Except for the expression of the plasma-derived exosomal miR-20b-5p, the expression patterns of exosomal miRNAs were concordant between plasma and serum, indicating the potential use of exosomal miRNAs as biomarkers.ConclusionWe identified four plasma miRNAs and four serum miRNAs from the miR-106a–363 cluster as promising novel biomarkers for the diagnosis of BC.Electronic supplementary materialThe online version of this article (10.1007/s10549-018-4757-3) contains supplementary material, which is available to authorized users.

miR‐205‐3p promotes proliferation and reduces apoptosis of breast cancer MCF‐7 cells and is associated with poor prognosis of breast cancer patients

“…Accumulative evidences indicate that a variety of miRNAs are involved in the regulation process of several tumors and play similar roles to tumor suppressor genes and oncogenes 22,23 The abnormal expressions of miR-21 and miR-205 are possibly related to the occurrence and development of breast cancer 12 Li et al 24 found that the miR-205 expression level is increased in epithelial ovarian cancer, and is closely related to the proliferation and invasion of ovarian cancer. In this study, we found that the level of miR-205-3p was significantly upregulated in breast cancer tissues, and further in vitro assay by overexpressing miR-205-3p validated its role on proliferation, invasion, and apoptosis of cancer cells, which was in line with previous findings 24 .…”

“…With the environmental deterioration and other factors, a younger trend of breast cancer occurrence has been shown in recent years20 The radical surgical resection, combined with radiotherapy and chemotherapy, marks the improvement regarding the survival time of early breast cancer patients, but its therapeutic effect is not satisfactory on advanced breast cancer patients 21 miRNA, as a kind of endogenous small noncoding RNA, plays an important role in cell differentiation, proliferation, and apoptosis through regulating the signaling pathway. In this study, we found that the level of miR-205-3p was significantly upregulated in breast cancer tissues, and further in vitro assay by overexpressing miR-205-3p validated its role on proliferation, invasion, and apoptosis of cancer cells, which was in line with previous findings24 .Our data showed that Ezrin and LaminA/C protein expressions in MCF-7 cells with miR-205-3p overexpression were significantly decreased compared with those in normal cells, which was consistent with previous finding 25 Ezrin protein is an important protein molecule in the ERM protein family, which, as a connexin between cytoskeleton and cell membrane, plays an important regulatory role in cell movement and adhesion, cytoskeletal remodeling, etc Ezrin protein also exerts important effects on the occurrence and metastasis of tumors26 It has been demonstrated that Ezrin functions as a prognostic factor and may predict potential lung metastasis in osteosarcoma and could also possibly be used as a new therapeutic target27 Ezrin is closely linked with the metastatic progression of cancer and is required in tumor-induced angio/lymphangiogenesis in vivo, which is frequently abnormally expressed in aggressive cancer types28 Interestingly, there is some controversy in the literature regarding the role of Ezrin in cancer metastasis and invasion. In this study, we found that the level of miR-205-3p was significantly upregulated in breast cancer tissues, and further in vitro assay by overexpressing miR-205-3p validated its role on proliferation, invasion, and apoptosis of cancer cells, which was in line with previous findings24 .Our data showed that Ezrin and LaminA/C protein expressions in MCF-7 cells with miR-205-3p overexpression were significantly decreased compared with those in normal cells, which was consistent with previous finding 25 Ezrin protein is an important protein molecule in the ERM protein family, which, as a connexin between cytoskeleton and cell membrane, plays an important regulatory role in cell movement and adhesion, cytoskeletal remodeling, etc Ezrin protein also exerts important effects on the occurrence and metastasis of tumors26 It has been demonstrated that Ezrin functions as a prognostic factor and may predict potential lung metastasis in osteosarcoma and could also possibly be used as a new therapeutic target27 Ezrin is closely linked with the metastatic progression of cancer and is required in tumor-induced angio/lymphangiogenesis in vivo, which is frequently abnormally expressed in aggressive cancer types28 Interestingly, there is some controversy in the literature regarding the role of Ezrin in cancer metastasis and invasion.…”

Extracellular vesicle microRNA cargo is correlated with HPV status in oropharyngeal carcinoma

“…Two other members of the miR‐106‐363 cluster were enriched in HPV + OPSCC‐derived EVs, miR‐106a‐5p and miR‐20b‐5p/miR‐20b‐3p. miR‐106a‐5p and miR‐20b‐5p have recently been shown to be upregulated in breast cancer tissues and enriched in circulating serum EVs of breast cancer patients . miR‐20b‐5p has been described as a core HPV upregulated miRNA because it is consistently upregulated in HPV + OPSCC and cervical cancer tissues .…”

Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery

“…TSE are considered major drivers of PMN formation and critical mediators of cancer cell—immune cell communication. Measurements of exosomal miRNA have been shown to accurately reflect tumor progression, and may serve as a prognostic tool among several cancers, for example, nonsmall cell lung cancer, hepatocellular cancer, gastric cancer, urinary bladder cancer and gliomas …”