The Interaction of NTN4 and miR-17-92 Polymorphisms on Breast Cancer Susceptibility in a Chinese Population.

INTRODUCTION: Genome-wide association studies have identified a genetic variant rs17356907 in netrin 4 (NTN4) as a risk locus of breast cancer (BC) in Europeans. NTN4 is a target gene of miR-17-92 cluster that is an oncogenic miRNA in BC development. We aimed to replicate the rs17356907 in a Chinese population and examine the interaction of NTN4 and miR-17-92 on BC susceptibility. MATERIALS AND METHODS: The rs17356907 in NTN4 and 3 additional polymorphisms in the promoter of miR-17-92 (ie, rs9588884, rs982873, and rs1813389) were determined in 415 patients with BC and 420 healthy controls using a TaqMan assay. The expression levels of NTN4 in BC and normal tissues were performed using the quantitative reverse transcription-PCR. RESULTS: With reference to the rs17356907AA genotype, the GG genotype was associated with a decreased risk of BC with an adjusted OR of 0.38 (95% CI: 0.20-0.74). With reference to the rs17356907AA-rs982873CT/CC genotypes, the rs17356907 AG/GG-rs982873CT/CC genotypes were associated with a borderline decreased risk of BC with an adjusted OR of 0.67 (95% CI: 0.48-0.93). Gene-gene interaction analysis showed that the rs17356907-rs982873-rs9588884-rs1813389 was the best model on BC susceptibility. Furthermore, the rs17356907GG genotype displayed higher levels of NTN4 mRNA. CONCLUSIONS: The NTN4 rs17356907 may have a single and interactive effect with miR-17-92 polymorphisms on the risk of BC.

Opposite response to hypoxia by breast cancer cells between cell proliferation and cell migration: A clue from microRNA expression profile.

The majority of tumors possess the features of hypoxia. It is generally accepted that hypoxia is a negative prognostic factor for cancer. Low levels of oxygen are able to modify basic cell metabolism status. Elucidating the basic response, including cell proliferation and migration, to hypoxia by cancer cells is important for understanding the role of hypoxia in the development of cancer. In the present study, CoCl2 stimulation was used to simulate hypoxia. A microRNA (miRNA/miR) array was used to systematically detect the changes in miRNA expression profiles. Following treatment with CoCl2 for 12 h, 15 miRNAs were markedly upregulated and 10 miRNAs were markedly decreased compared with the control. After 24 h CoCl2 incubation, 15 miRNAs were increased and 3 miRNAs were decreased compared with the control. Among them, 7 miRNAs were upregulated and 2 miRNAs were downregulated at 12 and 24 h following CoCl2 stimulation. The potential roles of these miRNA were reviewed and it was identified that the majority of them are associated with cell proliferation and migration. Additional experiments demonstrated that CoCl2 incubation inhibited the proliferation of MCF-7 cells but promoted cell migration. miR-491 may be a key miRNA for hypoxia-inhibited cell proliferation, as it was identified that hypoxia induced the downregulation of B-cell lymphoma-extra large in a miR-491-dependent manner. As the target of miR-302a, CXCR4 may be a key protein for hypoxia-promoted cell migration. In the present study, it was identified that in the early stage of hypoxia, cell proliferation was inhibited but cell migration was promoted. These results support the hypothesis that hypoxia may be a driving force for tumor cell escape from the primary tumor site to other organs, or other sites of the same organ.

Circular RNA hsa_circ_0001982 Promotes Breast Cancer Cell Carcinogenesis Through Decreasing miR-143.

Circular RNAs (circRNAs) are a type of noncoding RNAs generated from back-splicing, which have been verified to mediate multiple tumorigenesis. With the development of high-throughput sequencing, massive circRNAs are discovered in tumorous tissue. However, the potential physiological effect of circRNAs in breast cancer is still unknown. The purpose of this study is to investigate the expression profile of circRNA in breast cancer tissue and explore the in-depth regulatory mechanism in breast cancer tumorigenesis. In the present study, we screened the circRNA expression profiles in breast cancer tissue using circRNA microarray analysis. Totally 1705 circRNAs were identified to be significantly aberrant. Among these dysregulated circRNAs, hsa_circ_0001982 was markedly overexpressed in breast cancer tissue and cell lines. Bioinformatics analysis predicted that miR-143 acted as target of hsa_circ_0001982, which was confirmed by Dual-luciferase reporter assay. Loss-of-function and rescue experiments revealed that hsa_circ_0001982 knockdown suppressed breast cancer cell proliferation and invasion and induced apoptosis by targeting miR-143. In summary, our study preliminarily investigates the circRNA expression in breast cancer tissue and explores the role of competing endogenous RNA (ceRNA) mechanism in the progression, providing a novel insight for breast cancer tumorigenesis.