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CD47-SIRPα Signaling Induces Epithelial-Mesenchymal Transition and Cancer Stemness and Links to a Poor Prognosis in Patients with Oral Squamous Cell Carcinoma.

ABSTRACT: Oral squamous cell carcinoma (OSCC), with high mortality rates, is one of the most diagnosed head and neck cancers. Epithelial-to-mesenchymal transition (EMT) and the generation of cancer stem cells (CSCs) are two keys for therapy-resistance, relapse, and distant metastasis. Accumulating evidence indicates that aberrantly expressed cluster of differentiation (CD)47 is associated with cell-death evasion and metastasis; however, the role of CD47 in the generation of CSCs in OSCC is not clear. We investigated the functional roles of CD47 in OSCC cell lines SAS, TW2.6, HSC-3, and FaDu using the bioinformatics approach, immunoblotting, immunofluorescence staining, and assays for cellular migration, invasion, colony, and orosphere formation, as well as radiosensitivity. We demonstrated increased expression of CD47 in OSCC patients was associated with an estimated poorly survival disadvantage (p = 0.0391) and positively correlated with the expression of pluripotency factors. Silencing CD47 significantly suppressed cell viability and orosphere formation, accompanied by a downregulated expression of CD133, SRY-Box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and c-Myc. In addition, CD47-silenced OSCC cells showed reduced EMT, migration, and clonogenicity reflected by increased E-cadherin and decreased vimentin, Slug, Snail, and N-cadherin expression. Of therapeutic relevance, CD47 knockdown enhanced the anti-OSCC effect of radiotherapy. Collectively, we showed an increased CD47 expression promoted the generation of CSCs and malignant OSCC phenotypes. Silencing CD47, in combination with radiation, could provide an alternative and improved therapeutic efficacy for OSCC patients.

SUBMITTER: Pai S

PROVIDER: S-EPMC6952929 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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CD47-SIRPα Signaling Induces Epithelial-Mesenchymal Transition and Cancer Stemness and Links to a Poor Prognosis in Patients with Oral Squamous Cell Carcinoma.

Pai Shin S Bamodu Oluwaseun Adebayo OA Lin Yen-Kuang YK Lin Chun-Shu CS Chu Pei-Yi PY Chien Ming-Hsien MH Wang Liang-Shun LS Hsiao Michael M Yeh Chi-Tai CT Tsai Jo-Ting JT

Cells 20191217 12

<h4>Background</h4>Oral squamous cell carcinoma (OSCC), with high mortality rates, is one of the most diagnosed head and neck cancers. Epithelial-to-mesenchymal transition (EMT) and the generation of cancer stem cells (CSCs) are two keys for therapy-resistance, relapse, and distant metastasis. Accumulating evidence indicates that aberrantly expressed cluster of differentiation (CD)47 is associated with cell-death evasion and metastasis; however, the role of CD47 in the generation of CSCs in OSCC ...[more]

PMID: 31861233

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Project description:Rationale: Metastasis is the leading cause of disease-related death among patients with nasopharyngeal carcinoma (NPC). Mounting evidence suggest that epithelial-mesenchymal transition (EMT) is crucial for cancer cells to acquire metastatic ability. In this study, we aim to clarify the extent to which EMT is involved in various cancer properties and identify novel markers for predicting the prognosis of NPC patients. Methods: Two cellular models derived from the same NPC cell line with distinct metastasis ability were used for microarray analysis to identify key transcriptional factors that drive metastasis. Cell migration and invasion were analyzed by wound healing and Transwell analysis. Lung metatasis was determined by tail vein injection assay. Cancer stemness was analyzed using colony formation and xenograft assay. The EMT extent was evaluated using immunoblotting, RT-qPCR and immunofluorescence of EMT markers. The value of OVOL2 in prognosis was determined by immunohistochemistry in NPC biopsies. Results: OVOL2 was the most significantly down-regulated EMT transcription factor (EMT-TF) in cellular models of NPC metatasis. Low levels of OVOL2 were associated with poor overall survival of NPC patients and the reduced expression is partly due to promoter methylation and epithelial dedifferentiation. Knockout of OVOL2 in epithelial-like NPC cells partially activates EMT program and significantly promotes cancer stemness and metastatic phenotypes. Conversely, ectopically expression of OVOL2 in mesenchymal-like cells leads to a partial transition to an epithelial phenotype and reduced malignancy. Reversing EMT by depleting ZEB1, a major target of OVOL2, does not eliminate the stemness advantage of OVOL2-deficient cells but does reduce their invasion capacity. A comparison of subpopulations at different stages of EMT revealed that the extent of EMT is positively correlated with metastasis and drug resistance; however, only the intermediate EMT state is associated with cancer stemness. Conclusion: Distinct from other canonical EMT-TFs, OVOL2 only exhibits modest effect on EMT but has a strong impact on both metastasis and tumorigenesis. Therefore, OVOL2 could serve as a prognostic indicator for cancer patients.

Project description:BackgroundDiscs large homolog 5 (Dlg5) is a newly discovered member of the membrane-associated guanylate kinase superfamily (MAGUK) that is involved in several important processes, including the maintenance of epithelial cell polarity, cell proliferation control, and cell migration and invasion. Decreased expression of Dlg5 has been reported in malignancies arising from different organs. In the present study, we analyzed Dlg5 expression and its prognostic value in squamous cell lung cancer (SqCLC).MethodsTumor tissue and adjacent normal tissue sections were collected from 98 patients with SqCLC. The expression levels of Dlg5 and epithelial-mesenchymal transition (EMT) biomarkers in the tissue sections were examined by immunohistochemistry and western blot.ResultsThere were 80 males and 18 females in the study cohort. Patients at pathological stages I and IIIA accounted for 64.3% and 35.7% of the cohort, respectively. Western blot showed that Dlg5 expression differed between SqCLC and healthy tissues. Western blot also revealed low Dlg5 expression to be associated with low E-cadherin expression and high vimentin expression, which was consistent with the findings of immunohistochemical staining. Dlg5 expression was significantly correlated with lymph node (LN) metastasis (P=0.001) and disease recurrence (P<0.001), as well as with E-cadherin and vimentin expression (P=0.025 and P=0.001, respectively). Univariate analysis showed that overall survival was significantly correlated with the tumor-node-metastasis (P<0.001) and T (P=0.001) stages, LN metastasis (P<0.001), Dig5 expression (P<0.001), β-catenin expression (P=0.004), and vimentin expression (P=0.002). Patients with overexpression of Dlg5 and β-catenin had a more favorable prognosis than those without. Multivariate analysis revealed that tumor-node-metastasis stage [hazard ratio (HR) =2.124; 95% confidence interval (CI), 1.195-3.777; P=0.010], Dlg5 expression (HR =0.548; 95% CI, 0.313-0.959; P=0.035), β-catenin expression (HR =0.545; 95% CI, 0.312-0.953; P=0.033), and vimentin expression (HR =1.850; 95% CI, 1.050-3.258; P=0.033) could all independently predict the overall survival of patients with SqCLC.ConclusionsDlg5 is an important player in EMT which may have potential predictive value for SqCLC prognosis after surgery.

Dataset Information

CD47-SIRPα Signaling Induces Epithelial-Mesenchymal Transition and Cancer Stemness and Links to a Poor Prognosis in Patients with Oral Squamous Cell Carcinoma.

Publications

CD47-SIRPα Signaling Induces Epithelial-Mesenchymal Transition and Cancer Stemness and Links to a Poor Prognosis in Patients with Oral Squamous Cell Carcinoma.

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