Polymethoxylated Flavones from Orange Peels Inhibit Cell Proliferation in a 3D Cell Model of Human Colorectal Cancer

2018 ◽  
Vol 70 (2) ◽  
pp. 257-266 ◽  
Author(s):  
Inês Silva ◽  
Marta F. Estrada ◽  
Carolina V. Pereira ◽  
Andreia Bento da Silva ◽  
Maria R. Bronze ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cell Model ◽  
Human Colorectal Cancer ◽  
Orange Peels ◽  
Polymethoxylated Flavones ◽  
Inhibit Cell Proliferation

scholarly journals Polymethoxylated Flavones Target Cancer Stemness and Improve the Antiproliferative Effect of 5-Fluorouracil in a 3D Cell Model of Colorectal Cancer

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 326 ◽  
Author(s):  
Carolina Pereira ◽  
Marlene Duarte ◽  
Patrícia Silva ◽  
Andreia Bento da Silva ◽  
Catarina Duarte ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Colony Formation ◽  
Cell Model ◽  
Ht29 Cell ◽  
Cancer Stemness ◽  
Self Renewal ◽  
Cell Spheroids ◽  
Polymethoxylated Flavones ◽  
The Impact

Polymethoxylated flavones (PMFs) from citrus fruits are reported to present anticancer potential. However, there is a lack of information regarding their effect on cancer stem cell (CSC) populations, which has been recognized as responsible for tumor initiation, relapse, and chemoresistance. In this study, we evaluated the effect of an orange peel extract (OPE) and its main PMFs, namely, nobiletin, sinensetin, tangeretin, and scutellarein tetramethylether in targeting cell proliferation and stemness using a 3D cell model of colorectal cancer composed of HT29 cell spheroids cultured for 7 days in stirred conditions. Soft agar assay, ALDH1 activity, and relative quantitative gene expression analysis of specific biomarkers were carried out to characterize the stemness, self-renewal, and mesenchymal features of HT29 cell spheroids. Then, the impact of OPE and PMFs in reducing cell proliferation and modulating cancer stemness and self-renewal was assessed. Results showed that, when compared with monolayer cultures, HT29 cell spheroids presented higher ALDH1 activity (81.97% ± 5.27% compared to 63.55% ± 17.49% for 2D), upregulation of CD44, PROM1, SOX9, and SNAI1 genes (1.83 ± 0.34, 2.54 ± 0.51, 2.03 ± 0.15, and 6.12 ± 1.59 times) and high self-renewal capability (352 ± 55 colonies compared to 253 ± 42 for 2D). Incubation with OPE (1 mg/mL) significantly inhibited cell proliferation and modulated cancer stemness and self-renewal ability: colony formation, ALDH1 activity, and the expression of cancer stemness biomarkers PROM1 and LGR5 were significantly reduced (0.66 ± 0.15 and 0.51 ± 0.14 times, respectively). Among all PMFs, tangeretin was the most efficient in targeting the CSC population by decreasing colony formation and the expression of PROM1 and LGR5. Scutellarein tetramethylether was shown to modulate markers of mesenchymal/metastatic transition (increasing CDH1 and reducing ZEB1 and SNAI1) and nobiletin was capable of downregulating PROM1 and SNAI1 expression. Importantly, all PMFs and OPE were shown to synergistically interact with 5-fluorouracil, improving the antiproliferative response of this drug.

scholarly journals LncRNA HOTAIR is a Prognostic Biomarker for the Proliferation and Chemoresistance of Colorectal Cancer via MiR-203a-3p-Mediated Wnt/ß-Catenin Signaling Pathway

2018 ◽  
Vol 46 (3) ◽  
pp. 1275-1285 ◽  
Author(s):  
Zhigang Xiao ◽  
Zhan Qu ◽  
Zhikang Chen ◽  
Zhixue Fang ◽  
Ke Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Antisense Rna ◽  
Vital Role ◽  
Loss Of Function ◽  
Human Colorectal Cancer ◽  
Expression Levels ◽  
Lncrna Hotair

Background/Aims: HOX transcript antisense RNA (HOTAIR) plays a vital role in carcinogenesis. However, its functional and regulatory roles remain unclear. In this study, we aimed to investigate its biological function and clinical significance in human colorectal cancer (CRC). Methods: We examined the expression levels of lncRNA HOTAIR and miR-203a-3p in CRC tissues and CRC cell lines by qRT-PCR. Gain and loss-of-function assays were performed to examine the effects of HOTAIR and miR-203a-3p on the proliferation and chemoresistance of CRC cells. The possible mechanisms of HOTAIR were also explored by fluorescence reporter assay and Western blot. Results: The expressions of HOTAIR were upregulated in CRC tissue tissues compared to adjacent control tissues. We also found HOTAIR was downregulated by miR-203a-3p in CRC cell lines. Both HOTAIR knockdown and miR-203a-3p overexpression in CRC cell lines led to inhibited cell proliferation and reduced chemoresistance. We also determined that β-catenin and GRG5 were inhibitory targets of miR-203a-3p, and that Wnt/β-catenin signaling was inhibited by both HOTAIR knockdown and miR-203a-3p overexpression. Significantly, we found that increased expression of miR-203a-3p is essential for cell proliferation repression, chemoresistance reduction, and Wnt/β-catenin signaling inhibition induced by HOTAIR knockdown. Conclusions: Our study demonstrated that the lncRNA HOTAIR could regulate the progression and chemoresistance of CRC via modulating the expression levels of miR-203a-3p and the activity of Wnt/β-catenin signaling pathway.

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