Chaperone-mediated Autophagy Governs Progression of Papillary Thyroid Carcinoma via PPARγ-SDF1/CXCR4 Signaling

2020 ◽  
Vol 105 (10) ◽  
pp. 3308-3323
Author(s):  
Hong Zhou ◽  
Xin Xie ◽  
Ying Chen ◽  
Yi Lin ◽  
Zhaogen Cai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Papillary Thyroid Carcinoma ◽  
Tumor Cell Proliferation ◽  
Papillary Thyroid ◽  
Cxcr4 Signaling ◽  
Cell Proliferation And Migration ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Chaperone Mediated Autophagy ◽  
Proliferation And Migration

Abstract Context Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. Chaperone-mediated autophagy (CMA), 1 type of autophagy, is thought to promote or suppress cancer development in different cancer types. However, the effect of CMA on PTC development and the underlying mechanisms remain unknown. Objective To determine whether CMA plays implied critical roles in the development of PTC. Design We investigated the association between CMA and PTC development in PTC tissues and normal thyroid tissues by detecting the key protein of CMA, lysosome-associated membrane protein type 2A (LAMP2A), using quantitative polymerase chain reaction (PCR) and immunohistochemistry, which were further validated in the TGCA dataset. The effect of CMA on PTC development was studied by cell proliferation, migration, and apoptosis assays. The underlying mechanisms of peroxisome proliferator-activated receptor γ (PPARγ)-stromal cell-derived factor 1 (SDF1)/ C-X-C motif chemokine receptor 4 (CXCR4) signaling were clarified by western blotting, quantitative PCR, and rescue experiments. Knockdown and tamoxifen were used to analyze the effect of estrogen receptor (ER) α on CMA. Results Our study confirmed that CMA, indicated by LAMP2A expression, was significantly increased in PTC tumor tissues and cell lines, and was associated with tumor size and lymph node metastasis of patients. Higher CMA in PTC promoted tumor cell proliferation and migration, thereby promoting tumor growth and metastasis. These effects of CMA on PTC were exerted by decreasing PPARγ protein expression to enhance SDF1 and CXCR4 expression. Furthermore, CMA was found positively regulated by ERα signaling in PTC. Conclusion Our investigation identified CMA regulated by ERα promoting PTC tumor progression that enhanced tumor cell proliferation and migration by targeting PPARγ-SDF1/CXCR4 signaling, representing a potential target for treatment of PTC.

scholarly journals A 5′-tRNA halve, tiRNA-Gly promotes cell proliferation and migration via binding to RBM17 and inducing alternative splicing in papillary thyroid cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Litao Han ◽  
Hejing Lai ◽  
Yichen Yang ◽  
Jiaqian Hu ◽  
Zhe Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Alternative Splicing ◽  
Papillary Thyroid Cancer ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Papillary Thyroid ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background tRNA-derived small noncoding RNAs (sncRNAs) are mainly categorized into tRNA halves (tiRNAs) and fragments (tRFs). Biological functions of tiRNAs in human solid tumor are attracting more and more attention, but researches concerning the mechanisms in tiRNAs-mediated tumorigenesis are rarely. The direct regulatory relationship between tiRNAs and splicing-related proteins remain elusive. Methods Papillary thyroid carcinoma (PTC) associated tRNA fragments were screened by tRNA fragments deep sequencing and validated by qRT-PCR and Northern Blot in PTC tissues. The biological function of tRNA fragments were assessed by cell counting kit, transwells and subcutaneous transplantation tumor of nude mice. For mechanistic study, tRNA fragments pull-down, RNA immunoprecipitation, Western Blot, Immunofluorescence, Immunohistochemical staining were performed. Results Herein, we have identified a 33 nt tiRNA-Gly significantly increases in papillary thyroid cancer (PTC) based on tRFs & tiRNAs sequencing. The ectopic expression of tiRNA-Gly promotes cell proliferation and migration, whereas down-regulation of tiRNA-Gly exhibits reverse effects. Mechanistic investigations reveal tiRNA-Gly directly bind the UHM domain of a splicing-related RNA-binding protein RBM17. The interaction with tiRNA-Gly could translocate RBM17 from cytoplasm into nucleus. In addition, tiRNA-Gly increases RBM17 protein expression via inhibiting its degradation in a ubiquitin/proteasome-dependent way. Moreover, RBM17 level in tiRNA-Gly high-expressing human PTC tissues is upregulated. In vivo mouse model shows that suppression of tiRNA-Gly decreases RBM17 expression. Importantly, tiRNA-Gly can induce exon 16 splicing of MAP4K4 mRNA leading to phosphorylation of downstream signaling pathway, which is RBM17 dependent. Conclusions Our study firstly illustrates tiRNA-Gly can directly bind to RBM17 and display oncogenic effect via RBM17-mediated alternative splicing. This fully novel model broadens our understanding of molecular mechanism in which tRNA fragment in tumor cells directly bind RNA binding protein and play a role in alternative splicing.

scholarly journals Metformin Suppressed CXCL8 Expression and Cell Migration in HEK293/TLR4 Cell Line

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Zhihui Xiao ◽  
Wenjun Wu ◽  
Vladimir Poltoratsky
Keyword(s):  
Cell Proliferation ◽  
Cell Migration ◽  
Tumor Cell ◽  
Nuclear Translocation ◽  
High Dose ◽  
Dependent Manner ◽  
Tumor Cell Proliferation ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Chronic inflammation is associated with cancer. CXCL8 promotes tumor microenvironment construction through recruiting leukocytes and endothelial progenitor cells that are involved in angiogenesis. It also enhances tumor cell proliferation and migration. Metformin, type II diabetes medication, demonstrates anticancer properties via suppressing inflammation, tumor cell proliferation, angiogenesis, and metastasis. This study intended to address the role of metformin in regulation of CXCL8 expression and cell proliferation and migration. Our data indicated that metformin suppressed LPS-induced CXCL8 expression in a dose-dependent manner through inhibiting NF-κB, but not AP-1 and C/EBP, activities under the conditions we used. This inhibitory effect of metformin is achieved through dampening LPS-induced NF-κB nuclear translocation. Cell migration was inhibited by metformin under high dose (10 mM), but not cell proliferation.

scholarly journals MicroRNA-181a-5p Impedes IL-17-Induced Nonsmall Cell Lung Cancer Proliferation and Migration through Targeting VCAM-1

2017 ◽  
Vol 42 (1) ◽  
pp. 346-356 ◽  
Author(s):  
Yang Cao ◽  
Dan Zhao ◽  
Ping Li ◽  
Lanrong Wang ◽  
Bingli Qiao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Tumor Cell ◽  
Cell Lung Cancer ◽  
Nonsmall Cell Lung Cancer ◽  
Interleukin 17 ◽  
Tumor Cell Proliferation ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Aim: The contribution of the inflammatory mediator interleukin-17 (IL-17) in nonsmall cell lung cancer (NSCLC) malignancy has been reported in the literature. MicroRNA-181a-5p (miR-181a-5p) acts as a tumor suppressor which can regulate target gene at the posttranscriptional level. Our study aimed to investigate the interaction between IL-17 and miR-181a-5p in NSCLC. Methods: 35 patients with NSCLC and 24 COPD controls were selected and examined in our study. In vitro, H226 and H460 cell lines were exposed to different doses (20, 40, 60, and 80 ng/mL) of IL-17 to examine the effect of IL-17 on miR-181a-5p and vascular cell adhesion molecule 1 (VCAM-1) expression. MiR-181 mimic and miR-181a-5p inhibitor were transfected to explore the regulation of VCAM-1 as well as tumor cell proliferation and migration. Results: miR-181a-5p expression was downregulated, and IL-17 and VCAM-1 expression was upregulated in NSCLC tissues. Furthermore, IL-17 decreased miR-181a-5p expression but increased VCAM-1 expression in H226 and H460 cells. MiR-181 regulated VCAM-1 expression through binding to 3’-UTR sequence. MiR-181 attenuated tumor cell proliferation and migration. IL-17 modulated miR-181a-5p expression through activating NF-κB but not Stat3. Conclusion: Taken together, our data show the regulation of VCAM-1 expression by miR-181a-5p under IL-17 exposure, predicting a potential way for counteracting cancer metastasis.

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