Dataset Information

ALDHHIGH Population Is Regulated by the AKT/?-Catenin Pathway in a Cervical Cancer Model.

ABSTRACT: ALDH is an enzyme involved in different cellular processes, including cancer. It has been shown that a cellular subpopulation with high ALDH activity (ALDHHIGH) within a tumor is related to functional capabilities such as stemness, chemoresistance, and tumorigenicity. However, few studies have focused on determining the mechanisms behind ALDH activity within the cells. Previously, our group reported that ALDHHIGH cells have higher tumorigenicity in Cervical Cancer (CC) cell lines. Based on this, we were interested to know the molecular mediators of the ALDHHIGH cells, specifically ?-catenin, inasmuch as ?-catenin is regulated through different pathways, such as Wnt signaling, and that it acts as a transcriptional co-activator involved in cancer progression. In this work, we show that the increase in ALDHHIGH cell percentage is reverted by ?-catenin knockdown. Consistently, upon GSK3-? inactivation, a negative regulator of ?-catenin, we observed an increase in ALDHHIGH cells. Additionally, we observed a low percentage of cells positive for Fzd receptor, suggesting that in our model there is a low capacity to respond to Wnt ligands. The analysis of ALDHHIGH cells in a sphere formation model demonstrated the active state of AKT. In accordance with this, impairment of AKT activity not only reduced ?-catenin active state, but also the percentage of ALDHHIGH cells. This corroborates that AKT acts upstream of ?-catenin, thus affecting the percentage of ALDHHIGH cells. In conclusion, our results show that ALDHHIGH cells are dependent on ?-catenin, in spite of the Wnt pathway seems to be dispensable, while AKT emerges as central player supporting a mechanism in this important axis that is not yet well known but its analysis improves our understanding of ALDH activity on CC.

SUBMITTER: Sarabia-Sanchez MA

PROVIDER: S-EPMC7379485 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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ALDHHIGH Population Is Regulated by the AKT/β-Catenin Pathway in a Cervical Cancer Model.

Sarabia-Sánchez Miguel Ángel MÁ Alvarado-Ortiz Eduardo E Toledo-Guzman Mariel Esperanza ME García-Carrancá Alejandro A Ortiz-Sánchez Elizabeth E

Frontiers in oncology 20200717

ALDH is an enzyme involved in different cellular processes, including cancer. It has been shown that a cellular subpopulation with high ALDH activity (ALDHHIGH) within a tumor is related to functional capabilities such as stemness, chemoresistance, and tumorigenicity. However, few studies have focused on determining the mechanisms behind ALDH activity within the cells. Previously, our group reported that ALDHHIGH cells have higher tumorigenicity in Cervical Cancer (CC) cell ...[more]

PMID: 32766133

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Project description:Chondrosarcomas are malignant bone tumors refractory to chemotherapy and radiation treatment; thus, novel therapeutic strategies are required. Proline‑rich polypeptide 1 (PRP‑1) has previously demonstrated antitumor properties in chondrosarcoma. To further investigate the role of PRP‑1 in chondrosarcoma cells, its effects on cancer stem cell (CSC) populations were determined by analyzing aldehyde dehydrogenase (ALDH) activity, an established marker of CSCs, in association with regulation of the Wnt/β‑catenin signaling. A significant decrease in ALDHhigh CSCs was observed following treatment of chondrosarcoma JJ012 cells with PRP‑1. For RT2 profiler PCR array analysis of Wnt/β‑catenin signaling genes, cells were sorted into: i) Bulk JJ012 cells; ii) ALDHhigh cells sorted from untreated JJ012 cells (ALDHhigh‑untreated); and iii) ALDHlow cells sorted from PRP‑1‑treated JJ012 cells (ALDHlow‑PRP‑1). The expression levels of Wnt/β‑catenin signaling genes were determined to be downregulated in the ALDHhigh‑untreated cells and upregulated in ALDHlow‑PRP‑1 cells when compared to the bulk JJ012 cells. Additionally, two important oncogenes involved in this pathway, MMP7 and CCND2, were found to be downregulated in the ALDHlow‑PRP‑1 cells. Immunocytochemistry demonstrated the localization of β‑catenin in the nuclei of the PRP‑1‑treated cells. Western blotting indicated increased β‑catenin expression in the ALDHlow‑PRP‑1 cells compared with the bulk JJ012 cells. Analysis of the cytoplasmic and nuclear fractions of cells treated with increasing concentrations of PRP‑1 and β‑catenin nuclear translocation inhibitor CGP57380, suggested the nuclear translocation of β‑catenin following PRP‑1 treatment. In addition, treatment of JJ012 cells with a specific ALDH inhibitor, diethylaminobenzaldehyde, and PRP‑1 resulted in a significant decrease in cytoplasmic β‑catenin protein expression. This indicated that ALDH inactivation may be associated with the nuclear translocation of β‑catenin. Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway has been previously documented. The findings of the present study support the notion that Wnt/β‑catenin activation may serve a differential role in sarcomas, limiting tumor progression in association with decreased CSC activity.

Project description:Polymorphisms in microRNA (miRNA) genes could influence the expression of miRNAs that regulate the PI3K/Akt signalling pathway and play crucial roles in cancer susceptibility. To investigate the association of single nucleotide polymorphisms (SNPs) in miRNA genes of PI3K/Akt with cervical intraepithelial neoplasia (CIN) and cervical cancer (CC), nine SNPs located in miRNA genes were selected for genotyping, and the association of these SNPs with CIN and CC risk was evaluated. A total of 1,402 participants were enrolled in the current study, including 698 healthy individuals in the control group, 431 patients with CC, and 273 patients with CIN. Nine SNPs in miRNA genes (rs107822 in miR-219a, rs10877887 in let-7i, rs2292832 in miR-149, rs353293 in miR-143, rs3746444 in miR-499, rs3803808 in miR-132, rs4078756 in miR-10b, rs629367 in let-7a, and rs7372209 in miR-26a) were genotyped using MassArray, and the association of these SNPs with CIN and CC were analysed. The results showed that the frequencies of rs107822 in miR-219a and rs2292832 in miR-149 were significantly different between the control and CC groups (p < 0.005). The C allele of rs107822 in miR-219a was associated with an increased risk of CC (OR = 1.29, 95%CI:1.09-1.54) whereas the C allele of rs2292832 in miR-149 was associated with a decreased risk of CC (OR = 0.77, 95%CI:0.64-0.92). The results of inheritance model analysis showed that the best-fit inheritance models for rs107822 and rs2292832 were log-additive. The 2CC + CT genotype of rs107822 could be a risk factor for CC when compared with the TT genotype (OR = 1.28, 95%CI:1.08-1.51). The 2CC + CT genotype of rs2292832 could be a protective factor against CC when compared with the TT genotype (OR = 0.76, 95%CI:0.64-0.92). However, no association of these SNPs with CIN was found in the current study. Our results suggest that rs107822 in the promoter region of miR-219a and rs2292832 in pre-miR-149 region are associated with the risk of CC.

Project description:Background and Objective: Chemotherapy and radiotherapy are effective treatment options for cervical cancer (CC), but their efficacy is limited by short survival rate of about 5 years particularly for advance stage CC. Bioinformatics analysis combined with experimental in vivo and in vitro data can identify potential markers of tumorigenesis and cancer progression to improve CC prognosis and survival rate of the patients. This study aims to investigate the prognostic value of family with sequence similarity 83, member A (FAM83A) gene and miR-206 in promoting CC progression and the involved genetic signaling pathways. Method: This was a bioinformatic analysis study based on RNA sequencing data of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and verification by in vivo and in vitro experimental data. It was designed to evaluate whether the aberrantly expressed gene signatures could serve as new potential biomarker to improve prognosis prediction in CC. The TCGA RNA sequencing data [306 cervical squamous cell carcinoma (SCC) and endocervical adenocarcinoma samples and 13 adjacent samples] and GEO data (GSE9750 and GSE52903 datasets) were integrated and performed a bioinformatics analysis. Results: The results showed that CC-associated FAM83A gene serves as a key regulator of CC development and progression. Functionally, we observed that FAM83A is significantly overexpressed in CC, which is linked to poor overall survival as well as disease-free survival in CC patients. The in-vitro and in-vivo assessments performed after silencing FAM83A revealed that cell proliferation was significantly inhibited and the S-phase cell cycle arrest was induced. Mechanistically, FAM83A plays a role in PI3K/AKT signaling, and its downstream molecules could promote CC cell proliferation. Furthermore, functionality assessments by in-vitro luciferase reporter system and immunoblot analysis showed that miR-206 was the upstream of FAM83A and negatively correlated with FAM83A. Conclusion: The miR-206/FAM83A/PI3K/AKT signaling pathway possibly serves as a critical effector in CC progression indicating the potential prognostic value of FAM83A gene as a novel biomarker for CC progression.

Project description:BACKGROUND:Studies have shown that cancer susceptibility candidate 11 (CASC11), a newly discovered long non-coding RNA (lncRNA), was aberrantly overexpressed in hepatic carcinoma, gastric cancer and colorectal cancer. However, its effects on cervical cancer has been kept unknown up to now. The present study was aimed to investigate the relationship between lncRNA CASC11 and cervical cancer and further explore the mechanism of CASC11 effect on cervical cancer progression. MATERIALS:Quantitative real-time polymerase chain reaction (RT-qPCR) was used to detect the expressions of CASC11 in cancerous and adjacent normal tissues of patients with cervical cancer as well as in cell lines. The proliferation, migration, invasion and apoptosis were assayed after transfecting the cell with si-CASC11 or pcDNA3.1-CASC11. TOP/FOP-Flash luciferase reporter assay and western blot were used to analysis the activation of Wnt/?-catenin signaling pathway. Si-CASC11-transfected HeLa cells were subcutaneously inoculated into male athymic (nude) mice to investigate the effect of CASC11 on the tumor formation. RESULTS:We discovered that CASC11, the expression of which was positively associated with the tumor size and the FIGO staging and negatively related to the patients' survival rate, was up-regulated in the cervical cancer tissues and cell lines. Silencing CASC11 inhibited the proliferation, migration as well as invasion and promoted the cell apoptosis. Conversely, overexpression of CASC11 facilitated the cancer cell's proliferation, migration and invasion ability and suppressed the apoptosis. Further study showed that CASC11 promoted the migration and invasion of cervical cancer cells by activating Wnt/?-catenin signaling pathway and silencing CASC11 inhibited the tumor growth in vivo. CONCLUSION:Our study demonstrated that CASC11 promoted the cervical cancer progression by activating Wnt/?-catenin signaling pathway for the first time, which provides a new target or a potential diagnostic biomarker of the treatment for cervical cancer.

Dataset Information

ALDHHIGH Population Is Regulated by the AKT/?-Catenin Pathway in a Cervical Cancer Model.

Publications

ALDH<sup>HIGH</sup> Population Is Regulated by the AKT/β-Catenin Pathway in a Cervical Cancer Model.

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