scholarly journals microRNA-339-5p modulates Na+/I− symporter-mediated radioiodide uptake

2014 ◽  
Vol 22 (1) ◽  
pp. 11-21 ◽  
Author(s):  
Aparna Lakshmanan ◽  
Anna Wojcicka ◽  
Marta Kotlarek ◽  
Xiaoli Zhang ◽  
Krystian Jazdzewski ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Radioiodine Therapy ◽  
Expression Profiles ◽  
Hek293 Cells ◽  
Human Breast ◽  
Thyroid Cells ◽  
Promising Therapeutic Target ◽  
Rat Thyroid ◽  
Mcf 7

Na+/I−symporter (NIS)-mediated radioiodide uptake (RAIU) serves as the basis for targeted ablation of thyroid cancer remnants. However, many patients with thyroid cancer have reduced NIS expression/function and hence do not benefit from radioiodine therapy. microRNA (miR) has emerged as a promising therapeutic target in many diseases; yet, the role of miRs in NIS-mediated RAIU has not been investigated.In silicoanalysis was used to identify miRs that may bind to the 3′UTR of humanNIS(hNIS). The top candidate miR-339-5p directly bound to the 3′UTR of hNIS. miR-339-5p overexpression decreased NIS-mediated RAIU in HEK293 cells expressing exogenous hNIS, decreased the levels ofNISmRNA, and RAIU in transretinoic acid/hydrocortisone (tRA/H)-treated MCF-7 human breast cancer cells as well as thyrotropin-stimulated PCCl3 rat thyroid cells. Nanostring nCounter rat miR expression assay was conducted to identify miRs deregulated by TGFβ, Akti-1/2, or 17-AAG known to modulate RAIU in PCCl3 cells. Among 38 miRs identified, 18 were conserved in humans. One of the 18 miRs, miR-195, was predicted to bind to the 3′UTR of hNISand its overexpression decreased RAIU in tRA/H-treated MCF-7 cells. miR-339-5p was modestly increased in most papillary thyroid carcinomas (PTCs), yet miR-195 was significantly decreased in PTCs. Interestingly, the expression profiles of 18 miRs could be used to distinguish most PTCs from nonmalignant thyroid tissues. This is the first report, to our knowledge, demonstrating that hNIS-mediated RAIU can be modulated by miRs, and that the same miRs may also play roles in the development or maintenance of thyroid malignancy. Accordingly, miRs may serve as emerging targets to halt the progression of thyroid cancer and to enhance the efficacy of radioiodine therapy.

scholarly journals Crosstalk Between Abnormal TSHR Signaling Activation and PTEN/PI3K in the Dedifferentiation of Thyroid Cancer Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Fang Feng ◽  
Huiqin Han ◽  
Shuqi Wu ◽  
Hui Wang
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Mtor Signaling ◽  
Iodide Uptake ◽  
Thyroid Cells ◽  
Cell Mobility ◽  
Signaling Activation ◽  
Thyroid Cancer Cells ◽  
Serum Tsh

Iodide uptake and the metabolism of thyroid cells are regulated by thyrotropin (TSH)-TSH receptor (TSHR) signaling. Thus, it is necessary to elevate serum TSH levels by T4 withdraw or rTSH administration to facilitate radioiodide (131I) therapy for differentiated thyroid cancer (DTC). However, non-iodide-avid metastases of DTC which is dedifferentiated do not respond to stimulation by high levels of TSH, suggesting abnormal TSH-TSHR signal transduction in cancer cells. In addition, PI3K/AKT/mTOR signaling activation has been shown to be associated with the dedifferentiated phenotype of thyroid cancer, but the mechanism remains elusive. Therefore, in this study, we aimed to explore the role of abnormal TSH-TSHR signaling activation in regulating iodide uptake and cell mobility in thyroid cancer and its relationship with PI3K/AKT/mTOR signaling. We found that in thyroid cancer cells, TSH binds TSHR coupled to the Gα12/13 protein and then activates RhoA through interacting with leukemia associated RhoA guanine exchange factor (LARG). This results in a promigration tumorigenic phenotype independent of canonical TSHR-GαS signaling that regulates the expression of molecules involved in iodine uptake and metabolism. We observed that signaling pathways downstream of Gα12/13 signaling were increased, while that of Gαs signaling was decreased in thyroid cancer cells undergoing dedifferentiation compared to control cells following stimulation with different levels of TSH. PI3K/AKT/mTOR signaling activation enhanced Gα12/13 signaling through increasing LARG levels but also inhibited the expression of molecules downstream of Gαs signaling, including thyroid-specific molecules, and iodide uptake. In summary, our results demonstrate the noncanonical activation of TSH-TSHR signaling and its role in increasing the cell mobility and dedifferentiation of thyroid cancer through crosstalk with PI3K/AKT/mTOR signaling.

scholarly journals Dual Oncogenic/Anti-Oncogenic Role of PATZ1 in FRTL5 Rat Thyroid Cells Transformed by the Ha-RasV12 Oncogene

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 127 ◽  
Author(s):  
Michela Vitiello ◽  
Giuseppe Palma ◽  
Mario Monaco ◽  
Anna Bello ◽  
Simona Camorani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Thyroid Cancer ◽  
Cancer Cells ◽  
Tumor Growth Rate ◽  
Stem Cell Markers ◽  
Thyroid Cells ◽  
Mesenchymal Transition ◽  
Rat Thyroid ◽  
The Impact ◽  
Thyroid Cancer Cells

PATZ1 is a transcriptional factor downregulated in thyroid cancer whose re-expression in thyroid cancer cells leads to a partial reversion of the malignant phenotype, including the capacity to proliferate, migrate, and undergo epithelial-to-mesenchymal transition. We have recently shown that PATZ1 is specifically downregulated downstream of the Ras oncogenic signaling through miR-29b, and that restoration of PATZ1 in Ha-Ras transformed FRTL5 rat thyroid cells is able to inhibit their capacities to proliferate and migrate in vitro. Here, we analyzed the impact of PATZ1 expression on the in vivo tumorigenesis of these cells. Surprisingly, FRTL5-Ras-PATZ1 cells showed enhanced tumor initiation when engrafted in nude mice, even if their tumor growth rate was reduced compared to that of FRTL5-Ras control cells. To further investigate the cause of the enhanced tumor engraftment of FRTL5-Ras-PATZ1 cells, we analyzed the stem-like potential of these cells through their capacity to grow as thyrospheres. The results showed that restoration of PATZ1 expression in these cells increases stem cell markers’ expression and self-renewal ability of the thyrospheres while limiting their growth capacity. Therefore, we suggest that PATZ1 may play a role in enhancing the stem cell potential of thyroid cancer cells, but, at the same time, it impairs the proliferation of non-stem cells.

Long Noncoding RNA LINC00261 Induces Chemosensitization to Tamoxifen in Human Breast Cancer

2020 ◽  
Vol 10 (6) ◽  
pp. 789-797
Author(s):  
Zhaoyan Shi ◽  
Weidong Xiao ◽  
Meifang Hu
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Human Breast Cancer ◽  
Noncoding Rna ◽  
Quantitative Polymerase Chain Reaction ◽  
Chemotherapy Resistance ◽  
Migration And Invasion ◽  
Human Breast ◽  
Mcf 7

Breast cancer (BC) is one of the most prevalent and mortal malignancies in women worldwide, and tamoxifen is the mainstay treatment of breast cancer and the development of resistance represents a major obstacle for a cure. Long non-coding RNAs (LncRNAs) LINC00261 have been identified to serve a key role in the development of several tumors. However, the role of LINC00261 in breast cancer and chemotherapy resistance remains largely unknown. To investigate the role of LINC00261 in BC cells, LINC00261 was upregulated in MCF-7-TAM cells by transfecting with LINC00261 plasmid (pcDNA-LINCC00261). Subsequently, cell viability and drug sensitivity were measured using the CCK-8 assay. Reverse transcription-quantitative polymerase chain reaction (qRT-PCR) was performed to detect the level of LINC00261 in BC cells. Cell migration, invasion, and apoptosis were detected by Transwell, Scratch Test and Flow cytometry, respectively. Additionally, the associated protein expression was detected using Western blot. The results demonstrated that LINC00261 was significantly down-regulated in BC cells, especially in MCF-7-TAM cells. Overexpression of LINC00261 inhibited cell proliferation, migration, and invasion in MCF-7-TAM cells. Further, an abundant of LINC00261 sensitized breast cancer cells to tamoxifen and reduced tamoxifen-induced apoptosis in MCF-7-TAM cells. Finally, LINC00261 significantly regulated the protein expression of drug-resistant genes and the protein expression related to tumor metastasis and cell apoptosis. Therefore, this study revealed that LINC00261 induces chemosensitization to tamoxifen in human breast cancer, it may be a useful biomarker and potential therapeutic target.

scholarly journals Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer

2013 ◽  
Vol 21 (2) ◽  
pp. 161-173 ◽  
Author(s):  
Zongjing Zhang ◽  
Dingxie Liu ◽  
Avaniyapuram Kannan Murugan ◽  
Zhimin Liu ◽  
Mingzhao Xing
Keyword(s):  
Thyroid Cancer ◽  
Histone Acetylation ◽  
Underlying Mechanism ◽  
Histone Deacetylation ◽  
Braf V600e ◽  
Epigenetic Mechanism ◽  
Human Thyroid ◽  
Sodium Iodide Symporter ◽  
Thyroid Cells ◽  
Rat Thyroid

The BRAF V600E mutation causes impaired expression of sodium iodide symporter (NIS) and radioiodine refractoriness of thyroid cancer, but the underlying mechanism remains undefined. In this study, we hypothesized that histone deacetylation at the NIS (SLC5A5) promoter was the mechanism. Using the chromatin immunoprecipitation approach, we examined histone acetylation status on the lysine residues H3K9/14, H3K18, total H4, and H4K16 at the NIS promoter under the influence of BRAF V600E. We found that expression of stably or transiently transfected BRAF V600E inhibited NIS expression while the deacetylase inhibitor SAHA stimulated NIS expression in PCCL3 rat thyroid cells. Although BRAF V600E enhanced global histone acetylation, it caused histone deacetylation at the NIS promoter while SAHA caused acetylation in the cells. In human thyroid cancer BCPAP cells harboring homozygous BRAF V600E mutation, BRAF V600E inhibitor, PLX4032, and MEK inhibitor, AZD6244, increased histone acetylation of the NIS promoter, suggesting that BRAF V600E normally maintained histone in a deacetylated state at the NIS promoter. The regions most commonly affected with deacetylation by BRAF V600E were the transcriptionally active areas upstream of the translation start that contained important transcription factor binding sites, including nucleotides −297/−107 in the rat NIS promoter and −692/−370 in the human NIS promoter. Our findings not only reveal an epigenetic mechanism for BRAF V600E-promoted NIS silencing involving histone deacetylation at critical regulatory regions of the NIS promoter but also provide further support for our previously proposed combination therapy targeting major signaling pathways and histone deacetylase to restore thyroid gene expression for radioiodine treatment of thyroid cancer.

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