Scientific evidence linking vitamin D with various cancer types is growing, but the effects of vitamin D on ovarian cancer stem cell-like cells (CSCs) are largely unknown. The present study aimed to examine whether vitamin D was able to restrain the stemness of ovarian cancer. A side population (SP) from malignant ovarian surface epithelial cells was identified as CSCs, in vitro and in vivo. Furthermore, 1α,25-dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ] treatment inhibited the self-renewal capacity of SP cells by decreasing the sphere formation rate and by suppressing the mRNA expression levels of cluster of differentiation CD44, NANOG, OCT4, SOX2, Krüppel-like factor 4 and adenosine triphosphate binding cassette subfamily G member 2. Additionally, 1α,25(OH) 2 D 3 treatment decreased the expression of Cyclin D1, whereas it increased the expression of β-catenin and vitamin D receptor (VDR). Notably, immunofluorescence staining verified that 1α,25(OH) 2 D 3 promoted the expression of β-catenin in the cytoplasm. Furthermore, vitamin D 3 delayed the onset of tumor formation derived from injection of ovarian CSCs to nude mice, by reducing CD44 and enhancing β-catenin expressions in vivo. In conclusion, 1α,25(OH) 2 D 3 restrains the stem cell-like properties of ovarian cancer cells by enhancing the expression of VDR, by promoting the expression of β-catenin in the cytoplasm, and by suppressing the expression of CD44. These findings provide a novel insight into the functions of vitamin D in diminishing the stemness of cancer CSCs.
The radioresistance of tumors affect the outcome of radiotherapy. Accumulating data suggest that 1a,25(OH) 2 D 3 is a potential anti-oncogenic molecule in various cancers. In the present study, we investigated the radiosensitive effects and underlying mechanisms of 1a,25(OH) 2 D 3 in vitro and in vivo. We found that 1a,25(OH) 2 D 3 enhanced the radiosensitivity of lung cancer and ovarian cancer cells by promoting the NADPH oxidase-ROS-apoptosis axis. Compared to the group that only received radiation, the survival fraction and selfrenewal capacity of cancer cells treated with a combination of 1a,25(OH) 2 D 3 and radiation were decreased. Both apoptosis and ROS were significantly increased in the combination group compared with the radiation only group. Moreover, N-acetyl-L-cysteine, a scavenger of intracellular ROS, reversed the apoptosis and ROS induced by 1a,25(OH) 2 D 3 , indicating that 1a,25(OH) 2 D 3 enhanced the radiosensitivity of cancer cells in vitro by promoting ROSinduced apoptosis. Moreover, our results demonstrated that 1a,25(OH) 2 D 3 promoted the ROS level via activating NADPH oxidase complexes, NOX4, p22 phox , and p47 phox. In addition, knockdown of the vitamin D receptor (VDR) abolished the radiosensitization of 1a,25(OH) 2 D 3 , which confirmed that 1a,25(OH) 2 D 3 radiosensitized tumor cells that depend on VDR. Similarly, our study also evidenced that vitamin D 3 enhanced the radiosensitivity of cancer cells in vivo and extended the overall survival of mice with tumors. In summary, these results demonstrate that 1a,25(OH) 2 D 3 enhances the radiosensitivity depending on VDR and activates the NADPH oxidase-ROS-apoptosis axis. Our findings suggest that 1a,25 (OH) 2 D 3 in combination with radiation enhances lung and ovarian cell radiosensitivity, potentially providing a novel combination therapeutic strategy.
Endometrial carcinoma (EC) is one of the common gynecological cancers with increasing incidence and revived mortality recently. Given the heterogeneity of tumors and the complexity of lncRNAs, a panel of lncRNA biomarkers might be more precise and stable for prognosis. In the present study, we developed a new lncRNA model to predict the prognosis of patients with EC. EC-associated differentially expressed long noncoding RNAs (lncRNAs) were identified from The Cancer Genome Atlas (TCGA). Univariate COX regression and least absolute shrinkage and selection operator (LASSO) model were selected to find the 8-independent prognostic lncRNAs of EC patient. Furthermore, the risk score of the 3-lncRNA signature for overall survival (OS) was identified as CTD-2377D24.6 expression × 0.206 + RP4-616B8.5 × 0.341 + RP11-389G6.3 × 0.343 by multivariate Cox regression analysis. According to the median cutoff value of this prognostic signature, the EC samples were divided into two groups, high-risk set (3-lncRNAs at high levels) and low-risk set (3-lncRNAs at low levels), and the Kaplan–Meier survival curves demonstrated that the low-risk set had a higher survival rate than the high-risk set. In addition, the 3-lncRNA signature was closely linked with histological subtype (p = 0.0001), advanced clinical stage (p = 0.011), and clinical grade (p < 0.0001) in EC patients. Our clinical samples also confirmed that RP4-616B8.5, RP11-389G6.3, and CTD-2377D24.6 levels were increased in tumor tissues by qRT-PCR and in situ hybridization. Intriguingly, the p-value of combined 3-lncRNAs was lower than that of each lncRNA, indicating that the 3-lncRNA signature also showed higher performance in EC tissue than paracancerous. Functional analysis revealed that cortactin might be involved in the mechanism of 3-lncRNA signatures. These findings provide the first hint that a panel of lncRNAs may play a critical role in the initiation and metastasis of EC, indicating a new signature for early diagnosis and therapeutic strategy of uterine corpus endometrial carcinoma.
Mechanotransduction sensing of tissue architecture and cellular microenvironment is a fundamental regulator of cell fate, including cancer. Meanwhile, long noncoding RNAs (lncRNAs) play multifunctions during cancer development and treatment. However, the link between lncRNAs and cellular mechanotransduction in the context of cancer progression has not yet been elucidated. In this study, using atomic force microscopy (AFM), we find that ionizing radiation reduces tumor stiffness. Ionizing radiation-induced lncRNA CRYBG3 can blunt YAP/TAZ activity through interference with mechanotransduction, resulting in the inhibition of cell proliferation, invasion, and metastasis of lung cancer cells. In vivo, we found that loss of lncRNA CRYBG3 could power the tumor initiation and metastasis ability, but this was abolished by concomitant deplete TAZ. At the molecular level, lncRNA CRYBG3 that in turn dysregulates F-actin organization, activates the LATS1/2 kinase, all in all resulting in YAP/TAZ nuclear exclusion. Our research proposes that lncRNA CRYBG3 is a mediator of radiotherapy through its control of cancer-tissue mechanotransduction and wiring YAP/TAZ activity to control tumor growth and metastasis.
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