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Loss of BRCA1 Spontaneously Induces the Tumorigenesis in Lacrimal Gland.

ABSTRACT: Environmental and genetic factors exert important influences on lifespan and neoplastic transformation. We have previously shown that spontaneous tumors form frequently in mice homozygous for a full-length Brca1 deletion. In general, mutations of BRCA1 are closely associated with induction of breast and ovarian cancers but are also known to contribute to the incidence of other cancers at a low frequency. Female Brca1-mutant mice (Brca1co/coMMTV-cre) were generated by crossing Brca1 conditional knockout mice and MMTV-cre mice, and the occurrence of lacrimal gland abnormalities and tumors was followed until mice reached 18 months of age. Lacrimal gland tumors, which occur at a very low frequency in the human population (1 per 1,000,000 per year), were detected in 7 cases of Brca1co/coMMTV-cre mice (2.75%) older than 9 months of age. None of seven mice exhibited any abnormality in the mammary gland including neoplasia, suggesting lacrimal gland tumor is spontaneously and independently formed. These tumors, which were detected in seven mutant mice that displayed exophthalmoses, were malignant, originated from epithelial cells, and were identified as acinic cell carcinoma by pathological analysis. Further analysis revealed that tumorigenesis was accompanied by the accumulation of cyclin D1 and decreased expression of the cellular oncogenes, c-Myc, c-Jun, and c-Raf. Tumors also exhibited rearrangement of cytoskeletal proteins, including ?-catenin, keratin 5, and vimentin, depending on tumor progression. These results suggest that BRCA1 is involved in genetic stability of the lacrimal gland, providing new insight into genomic instability in organism maintenance and tumorigenesis of the lacrimal gland.

SUBMITTER: Kim SE

PROVIDER: S-EPMC6311772 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Loss of BRCA1 Spontaneously Induces the Tumorigenesis in Lacrimal Gland.

Kim Sun Eui SE Baek Hye Jung HJ Park Eun Jung EJ Lim Sung Chul SC Kim Sang Soo SS

Analytical cellular pathology (Amsterdam) 20181217

Environmental and genetic factors exert important influences on lifespan and neoplastic transformation. We have previously shown that spontaneous tumors form frequently in mice homozygous for a full-length Brca1 deletion. In general, mutations of BRCA1 are closely associated with induction of breast and ovarian cancers but are also known to contribute to the incidence of other cancers at a low frequency. Female Brca1-mutant mice (Brca1co/coMMTV-cre) were generated ...[more]

PMID: 30652068

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Project description:Background:Lacrimal adenoid cystic carcinoma (LACC) is one of the most common malignancies that affects lacrimal gland. MicroRNAs are known to play a crucial role as oncogenes or tumor suppressors. Specifically, miR-93 has been reported to play a crucial role in colorectal, breast, pancreatic, lung cancer and hepatocellular carcinoma. However, the role of miR-93 in LACC and the potential molecular mechanisms involved remain unknown. Therefore, we took the challenge to determine the involvement of miR-93 in the LACC by targeting BRMS1L. Method:A total of 5 adenoid cystic carcinoma (ACC) of lacrimal gland patient tissues and their plasma were examined. Three normal lacrimal glands and three normal serums were collected as a control group. After surgical resection, the specimens were preserved in liquid nitrogen and stored at -?80 °C until RNA extraction. Afterwards, LACC cells with miR-93-5p overexpression were subjected to qRT-PCR and western blot for epithelial-mesenchymal transition (EMT) markers levels. Ability of LACC cell migration, invasion, proliferation and apoptosis was examined by wounded healing, transwell, CCK-8 and apoptosis assays. Afterwards, TargetScan was used to predict putative targets of miR-93-5p. Then, the examination was performed whether miR-93-5p targets BRMS1L by the use of luciferase reporter assays and western blotting. Finally, immunohistochemical staining was sone and all the images were taken using a microscope (Nikon, Tokyo). Results:Our results showed that miR-93 was overexpressed in tissues and plasma of LACC patients compared to healthy controls. MiR-93 downregulated E-cadherin expression while increasing N-cadherin expression and significantly inhibited luciferase activity. Furthermore, western blotting results confirmed that miR-93-5p could inhibit BRMS1L expression. The BRMS1L staining in LACC tissues was weaker than in normal controls. In addition, miR-93-5p revealed a reverse correlation with the expression of BRMS1L. In addition, significant upregulation of E-cadherin and downregulation of N-cadherin were found when LACC cells were transfected with BRMS1L. Finally, miR-93-5p significantly enhanced TOP/FOP luciferase activity. Upregulation of BRMS1L reduced TOP/FOP luciferase activity while further overexpression of miR-93-5p could not rescue Wnt signaling activity. Conclusions:Our findings report that miR-93 promotes LACC cell migration, invasion, and proliferation via targeting downregulation of BRMS1L through regulation of Wnt signaling pathway.

Project description:BackgroundAqueous-deficient dry eye disease (ADDED) resulting from dysfunction of the lacrimal gland (LG) is currently incurable. Although LG stem/progenitor cell-based therapy is considered to be a promising strategy for ADDED patients, the lack of a reliable serum-free culture method to obtain enough lacrimal gland stem cells (LGSCs) and the basic standard of LGSC transplantation are obstacles for further research.MethodsAdult mouse LGSCs were cultured in Matrigel-based 3D culture under serum-free culture condition, which contained EGF, FGF10, Wnt3A, and Y-27632. LGSCs were continuously passaged over 40 times every 7 days, and the morphology and cell numbers were recorded. LGSCs were induced to differentiate to ductal cells by reducing Matrigel rigidity, while fetal bovine serum was used for the induction of acinar cells. RT-PCR or qRT-PCR analysis, RNA-sequence analysis, H&E staining, and immunofluorescence were used for characterization and examining the differentiation of LGSCs. LGSCs were allotransplanted into diseased LGs to examine the ability of repairing the damage. The condition of eye orbits was recorded using a camera, the tear production was measured using phenol red-impregnated cotton threads, and the engraftments of LGSCs were examined by immunohistochemistry.ResultsWe established an efficient 3D serum-free culture for adult mouse LGSCs, in which LGSCs could be continuously passaged for long-term expansion. LGSCs cultured from both the healthy and ADDED mouse LGs expressed stem/progenitor cell markers Krt14, Krt5, P63, and nestin, had the potential to differentiate into acinar or ductal-like cells in vitro and could engraft into diseased LGs and relieve symptoms of ADDED after orthotopic injection of LGSCs.ConclusionWe successfully established an efficient serum-free culture for adult mouse LGSCs aiming at LG repair for the first time. Our approach provides an excellent theoretical and technical reference for future clinical research for ADDED stem cell therapy.

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Dataset Information

Loss of BRCA1 Spontaneously Induces the Tumorigenesis in Lacrimal Gland.

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Loss of BRCA1 Spontaneously Induces the Tumorigenesis in Lacrimal Gland.

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