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Bioinformatics identification of the candidate microRNAs and construction of a competing endogenous RNA regulatory network in lacrimal gland adenoid cystic carcinoma high-grade transformation.

ABSTRACT: Adenoid cystic carcinoma of the lacrimal gland (LACC) is a major orbital malignancy. The recurrence rate and mortality rate are higher in LACC high-grade transformation (LACC-HGT) compared with in LACC. The present study aimed to identify the candidate microRNAs (miRNAs/miRs) and construct a competing endogenous RNA (ceRNA) regulatory network for LACC-HGT. A miRNA microarray on paraffin-embedded tissues was performed to identify the differentially expressed miRNAs (DEMs) of LACC-HGT. The overlap with the salivary adenoid cystic carcinoma miRNA/RNA sequencing dataset in the Gene Expression Omnibus was used to identify candidate miRNAs. In order to construct a ceRNA regulatory network of LACC-HGT, a microarray of mRNA and circRNA in primary cell lines was performed. The circRNAs and genes with high expression in LACC-HGT were predicted as targeting miRNAs, and the circRNA-miRNA-mRNA regulatory network was constructed. miR-140-3p was identified as part of the ceRNA network and as a candidate miRNA, therefore this was further analyzed using reverse transcription-quantitative (RT-q)PCR. Overall, the Agilent Human microarray analysis identified a total of 16 DEMs from the LACC-HGT paraffin-embedded tissues. A total of 653 DECs and 9,566 DEGs of LACC-HGT primary cell lines were screened via the microarray of mRNA and circRNA. The ceRNA regulatory network was constructed using the cross-binding of circRNA-miRNA, miRNA-mRNA and the downregulated miRNAs in LACC-HGT to clearly demonstrate the circRNA-miRNA-mRNA interaction relationship. RT-qPCR results confirmed that miR-140-3p was downregulated in LACC-HGT tissues and primary cell lines compared with LACC. Target genes CD200 and parathyroid hormone-related protein were significantly upregulated in LACC-HGT primary cell lines. miR-140-3p and its target genes may play an important role in LACC-HGT pathogenesis. In conclusion, the current bioinformatics study constructed a ceRNA network based on a microarray, which may help identify novel miRNA therapeutic targets for LACC-HGT.

SUBMITTER: Jiang M

PROVIDER: S-EPMC7967933 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Bioinformatics identification of the candidate microRNAs and construction of a competing endogenous RNA regulatory network in lacrimal gland adenoid cystic carcinoma high-grade transformation.

Jiang Meixia M Liu Xun X Zhang Chuanli C Zhu Limin L Wu Hai-Dong HD Dong Lijie L Wang Tingting T Lin Tingting T He Yanjin Y

Oncology letters 20210308 5

Adenoid cystic carcinoma of the lacrimal gland (LACC) is a major orbital malignancy. The recurrence rate and mortality rate are higher in LACC high-grade transformation (LACC-HGT) compared with in LACC. The present study aimed to identify the candidate microRNAs (miRNAs/miRs) and construct a competing endogenous RNA (ceRNA) regulatory network for LACC-HGT. A miRNA microarray on paraffin-embedded tissues was performed to identify the differentially expressed miRNAs (DEMs) of LACC-HGT. The overlap ...[more]

PMID: 33747217

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Project description:BackgroundLacrimal 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.MethodA 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).ResultsOur 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.ConclusionsOur 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:PurposeAdenoid cystic carcinoma (ACC) in the lacrimal gland is a rare malignancy. P16 is encoded by the CDKN2A gene, which is recognized as a tumor suppressor due to its inactivation in many types of tumors. However, p16 overexpression is also linked to adverse tumor parameters. These contradictory observations have also been confirmed in ACCs in the salivary glands. Furthermore, evidence of human papilloma virus (HPV) infection is found in a proportion of ACCs in the salivary glands. P16 is often overexpressed in HPV-related squamous cell carcinoma in parallel. To our knowledge, the role of p16 and HPV in ACCs in the lacrimal gland is still unknown.MethodsTwenty-one ACCs in the lacrimal gland and ten matched healthy lacrimal glands were studied. P16 was detected with immunohistochemistry (IHC), and HPV was detected with in situ hybridization (ISH) and PCR in all cases. Other cell cycle proteins were also detected with IHC, including cyclin D1 and Ki67. The methylation status of the p16 promoter was detected with methylation-specific PCR (MSP) to further investigate the regulation of p16 expression.ResultsThe expression rates of p16 (47.6%, 10/21), cyclin D1 (100%, 21/21), and Ki67 (52.4%, 11/21) were increased in ACCs compared to healthy lacrimal glands (negative). The results showed p16 expression was limited to the inner ductal epithelial cells in the majority of the tubular and cribriform patterns. In solid ACCs, p16 was uniformly positive. HPV was negative in all 21 cases with ISH and PCR. P16 overexpression was associated with cyclin D1 overexpression (p=0.013). Only 13 cases were tested successfully with MSP. The expression rate of p16 methylation was 23.1% (3/13) of the ACCs. Compared with primary ACCs, recurrent ACCs showed higher p16, cyclin D1, and Ki67 expression (p=0.011, p=0.026, p=0.049, respectively).ConclusionsIn summary, p16 overexpression was cell-type dependent in ACCs in the lacrimal gland, while HPV infection was negative. P16 overexpression was unrelated to HPV infection. The mechanism of p16 overexpression needs to be further investigated in ACCs in the lacrimal gland.

Project description:Adenoid cystic carcinoma (ACC) is a slow growing, but relentless cancer. Due to its rarity and lack of understanding of its molecular etiology, no standard chemotherapy for ACC currently exists and many patients suffer from recurrent and/or metastatic disease. As such, development of safe and effective therapies is imperative. To describe and summarize existing clinical trial studies and preclinical discoveries, we surveyed the PubMed on developmental therapeutics for ACC. Objective response rates to monotherapy with cytotoxic agents were approximately 10% with cisplatin, 5-FU, gemcitabine, mitoxantrone, epirubicin, vinorelbine and paclitaxel. The most studied combination therapies were cyclophosphamide-doxorubicin-cisplatin (CAP) and cisplatin-vinorelbine, with an objective response rate of 18-31%. Among molecularly targeted drugs, the most studied drugs are inhibitors targeting the vascular endothelial growth factor receptor (VEGFR) to inhibit tumor angiogenesis. Among those, lenvatinib and axitinib showed a relatively high objective response rate of 11-16% and 9-17%, respectively. Given high recurrence rates and chemoresistance of ACC, treatments targeting cancer stem cells (CSC), which function as tumor-initiating cells and drive chemoresistance, may be particularly valuable. CSC have been shown to be targetable via MYB, Notch1, p53 and epigenetic mechanisms. Myb overexpression is characteristic in ACC but was previously thought to present a difficult target due to its nature as a transcription factor. However, due to the development Myb-targeted inhibitors and an ongoing clinical trial of MYB-targeted cancer vaccine therapy, MYB is becoming an increasingly attractive therapeutic target. Drugs targeting NOTCH signaling demonstrated 5-17% response rate in phase I clinical trials. Within the field of epigenetics, treatment with PRMT5 inhibitors has shown 21% partial response rate in phase I clinical trial. Immunotherapies, such as PD-1 inhibitors, are also associated with CSC, but have not been effective against ACC. However, clinical trials of cancer vaccine therapies are actively being conducted. In addition to conventional chemotherapies and inhibitors of angiogenesis, the emergence of new therapies such as immunotherapy and those targeting cancer stemness is expected to bring clinical benefits to patients in the future.

Dataset Information

Bioinformatics identification of the candidate microRNAs and construction of a competing endogenous RNA regulatory network in lacrimal gland adenoid cystic carcinoma high-grade transformation.

Publications

Bioinformatics identification of the candidate microRNAs and construction of a competing endogenous RNA regulatory network in lacrimal gland adenoid cystic carcinoma high-grade transformation.

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