Sulforaphane targets cancer stemness and tumor initiating properties in oral squamous cell carcinomas via miR-200c induction

Liu, Chia‐Ming; Peng, Cheng-Ming; Liao, Yi-Wen; Lu, Michael S.-C.; Tsai, Meng-Lun; Yeh, Jung‐Chun; Yu, Chuan‐Hang; Yu, Cheng–Chia

doi:10.1016/j.jfma.2016.01.004

Cited by 55 publications

(32 citation statements)

References 39 publications

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“…Similar results with this ITC had already been reported in a panel of human primary CRC cell lines, in which impairment of anchorage-independent cell growth in vitro was also dose-dependent, and confirmed in vivo [21]. Besides, the effect of SFN in self-renewal, metastatic and tumor initiation skills in oral squamous cell carcinoma and pancreatic cancer stem-like cells were also already reported in vitro and in vivo [26,27]. …”

Section: Resultssupporting

confidence: 87%

“…Despite the cumulative evidences on SFN effect in ALDH1 activity of cancer stem-like cells of other solid tumors [26,27,28,29], in our experiments the effect of this ITC, either directly or indirectly through the extract, was not verified in the context of HT29 spheroids enriched in stem-like cells. As shown in Figure 5A, in the doses tested, broccoli extract and SFN did not demonstrated potential to impair ALDH1 activity and to target ALDH + cells.…”

Section: Resultscontrasting

confidence: 87%

“…Moreover, both ITCs have also proved to exert anticancer effects and target CSCs of several solid tumors [26,27,28,29,30]. However, despite the recognized role of these ITCs in the modulation of several cellular processes in CRC cells related with tumor progression, little is known about the effect of these phytochemicals in CRC stem-like cells.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Pereira

Silva²,

Duarte³

et al. 2017

Nutrients

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Colorectal cancer (CRC) recurrence is often attributable to circulating tumor cells and/or cancer stem cells (CSCs) that resist to conventional therapies and foster tumor progression. Isothiocyanates (ITCs) derived from Brassicaceae vegetables have demonstrated anticancer effects in CRC, however little is known about their effect in CSCs and tumor initiation properties. Here we examined the effect of ITCs-enriched Brassicaceae extracts derived from watercress and broccoli in cell proliferation, CSC phenotype and metastasis using a previously developed three-dimensional HT29 cell model with CSC-like traits. Both extracts were phytochemically characterized and their antiproliferative effect in HT29 monolayers was explored. Next, we performed cell proliferation assays and flow cytometry analysis in HT29 spheroids treated with watercress and broccoli extracts and respective main ITCs, phenethyl isothiocyanate (PEITC) and sulforaphane (SFN). Soft agar assays and relative quantitative expression analysis of stemness markers and Wnt/β-catenin signaling players were performed to evaluate the effect of these phytochemicals in stemness and metastasis. Our results showed that both Brassicaceae extracts and ITCs exert antiproliferative effects in HT29 spheroids, arresting cell cycle at G2/M, possibly due to ITC-induced DNA damage. Colony formation and expression of LGR5 and CD133 cancer stemness markers were significantly reduced. Only watercress extract and PEITC decreased ALDH1 activity in a dose-dependent manner, as well as β-catenin expression. Our research provides new insights on CRC therapy using ITC-enriched Brassicaceae extracts, specially watercress extract, to target CSCs and circulating tumor cells by impairing cell proliferation, ALDH1-mediated chemo-resistance, anoikis evasion, self-renewal and metastatic potential.

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Section: Resultssupporting

confidence: 87%

Section: Resultscontrasting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Pereira

Silva²,

Duarte³

et al. 2017

Nutrients

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“…Therefore, it is necessary to identify and employ novel biomarkers as possible therapeutic targets or prognostic predictors, which will be used as an adjunct to the staging system and contribute to the optimization of treatment for patients with NSCLC. miRNAs as a recent focus in tumor research serve an oncogenic or tumor-suppressive role in different cancer types via various pathways (17)(18)(19). miR-200c is a member of the miR-200 family, which is located on chromosome 12p13 and is closely associated with carcinogenesis and disease progression in a wide range of cancer types (20,21).…”

Section: Discussionmentioning

confidence: 99%

Potential use of microRNA-200c as a prognostic marker in non-small cell lung cancer

Tian

Yue

et al. 2017

Oncology Letters

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Abstract. MicroRNAs (miRNAs/miRs) are a class of small, highly conserved non-coding RNAs that can serve either oncogenic or tumor-suppressive roles in a wide variety of tumors. miR-200c is a member of the miR-200 family whose specific role in non-small cell lung cancer (NSCLC) has not yet been elucidated. The purpose of the present study was to detect the expression level of miR-200c in NSCLC, and to analyze its association with clinicopathological factors and patient prognosis. The present study determined the expression levels of miR-200c in 110 tumor samples collected from patients diagnosed with NSCLC who underwent complete tumor resection with regional lymph node dissection, as assessed by reverse transcription-quantitative polymerase chain reaction. The association between the expression level of miR-200c and clinicopathological features and patient prognosis was also analyzed. The results showed that miR-200c overexpression was detected in 66 of the 110 cases and was significantly associated with positive lymph node metastasis (P<0.001). Univariate survival analysis demonstrated that high miR-200c expression, positive lymph node metastasis and advanced Tumor-Node-Metastasis (TNM) classification stage significantly predicted decreased 5-year disease-free survival rates (all P<0.05) and poor 5-year overall survival rates (all P<0.01), respectively. The results of multivariate Cox regression analysis showed that TNM stage and miR-200c expression retained its significance as an independent prognostic factor for unfavorable 5-year disease-free survival rates (P<0.05) and poor 5-year overall survival rates (P<0.01). The present findings suggest that miR-200c overexpression is significantly associated with poor survival rates in NSCLC and that miR-200c could play an oncogenic role. miR-200c may have clinical potential as a promising prognostic predictor for patients with NSCLC.

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“…In recent years, many studies have revealed that miRNAs play an important physiological and pathological role in cancers; thus, therapies targeting miRNAs may be an effective strategy to block cancer oncogenesis and progression. Several miRNAs have previously been shown to be regulated by sulforaphane [8][9][10] . Sulforaphane can modify the activity of miR-200c/ ZEB1 and the snail pathway to affect epithelial-mesenchymal transition (EMT) [11] , suggesting that sulforaphane may target specific miRNAs to promote its anti-metastatic effects in cancers.…”

Section: Introductionmentioning

confidence: 99%

Sulforaphane suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated GSK3β/β-catenin signaling pathways

et al. 2016

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Sulforaphane is a common antioxidant selectively abundant in cruciferous plants, which exhibits effective anti-cancer actions in control of tumorigenesis or progression of various cancers. A recent study has shown that sulforaphane attenuates the EGFR signaling pathway in non-small cell lung cancer (NSCLC), suggesting its potential anti-metastatic effects. In this study we assessed the involvement of sulforaphane and miR-616-5p in epithelial-mesenchymal transition (EMT) and NSCLC metastasis. Sulforaphane suppressed the cell proliferation in human NSCLC cell lines H1299, 95C and 95D with IC 50 values of 9.52±1.23, 9.04±1.90 and 17.35±2.03 μmol/L, respectively. At low concentrations (1-5 μmol/L), sulforaphane dose-dependently inhibited the migration and invasion of 95D and H1299 cells with relatively high metastatic potential. The anti-metastatic action of sulforaphane was confirmed in 95D and H1299 cell xenografts in vivo. In fresh NSCLC tissue samples from 179 patients, miR-616-5p levels were upregulated in late-stage NSCLCs, and strongly correlated with risk of NSCLC recurrence and metastasis. Consistent with the clinic observation, miR-616-5p levels in the 3 NSCLC cell lines were correlated with their metastatic ability, and were decreased by sulforaphane treatment. Silencing miR-616-5p markedly suppressed the migration and invasion of 95D cells in vitro and NSCLC metastasis in vivo. Further studies revealed that miR-616-5p directly targeted GSK3β and decreased its expression, whereas sulforaphane decreased miR-616-5p levels by histone modification, and followed by inactivation of the GSK3β/β-catenin signaling pathway and inhibition of EMT, which was characterized by loss of epithelial markers and acquisition of a mesenchymal phenotype in NSCLC cells. Our findings suggest that sulforaphane is a potential adjuvant chemotherapeutic agent for the prevention of NSCLC recurrence and metastasis, and miR-616-5p can be clinically utilized as a biomarker or therapeutic target to inhibit metastasis.

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Sulforaphane targets cancer stemness and tumor initiating properties in oral squamous cell carcinomas via miR-200c induction

Abstract: These lines of evidence suggest that sulforaphane can suppress the cancer stemness and tumor-initiating properties in OSCC-CSCs both in vitro and in vivo.

Cited by 55 publications

References 39 publications

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Potential use of microRNA-200c as a prognostic marker in non-small cell lung cancer

Sulforaphane suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated GSK3β/β-catenin signaling pathways

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