MicroRNA 345 (miR345) regulates KISS1-E-cadherin functional interaction in breast cancer brain metastases. (1st July 2020)

• Record Type: Journal Article
• Authors: Ulasov, Ilya; Borovjagin, Anton; Fares, Jawad; Yakushov, Semyon; Malin, Dmitry; Timashev, Peter; Lesniak, Maciej S.
• Is Part Of: Cancer letters. Volume 481(2020)
• Page Start: 24
• Page End: 31
• Publication Date: 2020-07-01
• Subjects: Breast cancer -- Metastases -- KISS1 metastatic tumor suppressor -- E-cadherin; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.03.025
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Brain metastases manifest the advanced stage of breast cancer disease with poor prognosis for patient survival. Recent reports demonstrate that some therapeutic agents can activate the expression of several breast cancer-associated genes, whose products are involved in the onset and development of brain metastases. In this study, we discovered a functional link between KISS1 and E-cadherin that could be observed in both primary brain metastatic lesions and paired cell lines, such as parental CN34TGL and MDA-MB-231 and their respective brain metastatic subclones CN34Brm2Ctgl and MDA-MB-231Br. Remarkably, expression of KISS1 and E-cadherin genes consistently showed an inverse correlation in all of the above cell/tissue types. While E-cadherin expression was strongly upregulated in metastatic clones isolated from blood and brain, the levels of this protein in parental MDA-MB-231 cell line was low. Furthermore, E-cadherin upregulation can be artificially induced in MDA-MB-231Br and CN34Brm2Ctgl cell populations by knocking down KISS1 expression directly or through overexpressing the miR345 mimic. In the aggregate, our data suggest that the tumor microenvironment, which controls breast cancer spreading via miR345-regulated KISS1 expression, might modulate metastatic spreading by a mechanism(s) involving upregulation of E-cadherin production. Highlights: KISS1 and E-cadherin expression levels exhibit an inverse correlation in the primary patient samples. KISS1 inhibition induces E-cadherin. MiR345 induces E-cadherin expression via KISS1 suppression on the mRNA level. Downregulation of KISS1 induces cancer cell resistance to ionizing radiation and chemotherapy (temozolomide).