Extracellular vesicle-carried GTF2I from mesenchymal stem cells promotes the expression of tumor-suppressive FAT1 and inhibits stemness maintenance in thyroid carcinoma

doi:10.1007/s11684-023-0999-5

2023, Vol. 17

Issue (6) : 1186-1203 https://doi.org/10.1007/s11684-023-0999-5

Extracellular vesicle-carried GTF2I from mesenchymal stem cells promotes the expression of tumor-suppressive FAT1 and inhibits stemness maintenance in thyroid carcinoma

Jie Shao¹, Wenjuan Wang², Baorui Tao¹, Zihao Cai¹, Haixia Li², Jinhong Chen¹(

)

¹. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
². Department of Pathology, Huashan Hospital, Fudan University, Shanghai 200040, China

Download: PDF(10812 KB) HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Abstract

Through bioinformatics predictions, we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma (TC). Further, Pearson’s correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression. Therefore, we selected them for this present study, where the effects of bone marrow mesenchymal stem cell-derived EVs (BMSDs-EVs) enriched with GTF2I were evaluated on the epithelial–to–mesenchymal transition (EMT) and stemness maintenance in TC. The under-expression of GTF2I and FAT1 was validated in TC cell lines. Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells, EMT, and stemness maintenance. Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression. MSC-EVs could shuttle GTF2I into TPC-1 cells, where GTF2I inhibited TC malignant phenotypes, EMT, and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation. In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice. Taken together, our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.

Keywords thyroid carcinoma mesenchymal stem cell extracellular vesicle GTF2I FAT1 CDK4

Corresponding Author(s): Jinhong Chen

Just Accepted Date: 04 July 2023 Online First Date: 13 September 2023 Issue Date: 06 February 2024

Cite this article:

Jie Shao,Wenjuan Wang,Baorui Tao, et al. Extracellular vesicle-carried GTF2I from mesenchymal stem cells promotes the expression of tumor-suppressive FAT1 and inhibits stemness maintenance in thyroid carcinoma[J]. Front. Med., 2023, 17(6): 1186-1203.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-0999-5
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I6/1186

Fig.1 FAT1 overexpression blunts the oncogenic phenotypes, EMT, and stemness maintenance of TC cells. (A) Venn diagram of the poorly expressed DEGs in the TC-related TCGA data and TC-related genes retrieved from the GeneCards and Phenolyzer databases. (B) GO and KEGG enrichment analysis of the 345 candidate genes. The abscissa represents the gene ratio. (C) Pathway–gene network. Blue represents KEGG pathway, and yellow represents genes. (D) Forest map of the univariate Cox regression analysis results. (E) The mRNA expression of FAT1 in the normal samples (blue box; n = 58) and TC samples (yellow box; n = 510). (F) RT-qPCR detection of FAT1 expression in TC tissues and adjacent tissues. (G) RT-qPCR detection of FAT1 expression in TC cell lines (TPC-1, 8305C, CAL62, and IHH4) and normal thyroid cell line Nthy-ori 3-1. (H) Transduction efficiency of oe-FAT1 in TPC-1 cells verified by RT-qPCR and Western blot analyses. (I) Clonogenic potential of TPC-1 cells overexpressing FAT1 measured by colony formation assay. (J) Migration and invasion of TPC-1 cells overexpressing FAT1 measured by Transwell assays. (K) Western blot analysis of EMT-related proteins Vimentin, slug, snail, E-cadherin, and N-cadherin in TPC-1 cells overexpressing FAT1. (L) Stemness maintenance in TPC-1 cells overexpressing FAT1 measured by sphere formation experiment. (M) Western blot analysis of stemness-related proteins CD133, Oct4, ALDH1A1, and c-Myc in TPC-1 cells overexpressing FAT1. **P < 0.01, ***P < 0.001, and ****P < 0.0001. The cell experiment was conducted three times independently.

Fig.2 GTF2I upregulates the expression of FAT1 by binding to the promoter region of FAT1. (A) Venn diagram of the TC-related genes and hTFtarget prediction results. (B) Expression of 11 candidate transcription factors in the normal samples (blue box; n = 58) and TC samples (yellow box; n = 510). (C) Correlation of GTF2I expression with FAT1 expression in TC samples analyzed by Pearson’s correlation coefficient. (D) RT-qPCR detection of GTF2I expression in TC tissues and adjacent tissues. (E) RT-qPCR detection of GTF2I expression in TC cell lines (TPC-1, 8305C, CAL62, and IHH4) and normal thyroid cell line Nthy-ori 3-1. (F) Transduction efficiency of oe-GTF2I and sh-GTF2I in TPC-1 cells verified by RT-qPCR. (G) RT-qPCR detection of GTF2I expression in TPC-1 cells with oe-GTF2I or sh-GTF2I. (H) Binding of GTF2I to the promoter region of FAT1 confirmed by dual-luciferase reporter assay. (I) Enrichment of GTF2I in the promoter region of FAT1 in TPC-1 cells measured by ChIP assay. ***P < 0.001, and ****P < 0.0001. The cell experiment was conducted three times independently.

Fig.3 GTF2I restricts the oncogenic phenotypes, EMT, and stemness maintenance of TC cells by upregulating FAT1 expression. (A) RT-qPCR detection of GTF2I and FAT1 expression in TPC-1 cells transduced with oe-GTF2I, oe-GTF2I + sh-FAT1-1, and oe-GTF2I + sh-FAT1-2. (B) Clonogenic potential of TPC-1 cells transduced with oe-GTF2I alone or combined with sh-FAT1-1 measured by colony formation assay. (C) Migration and invasion of TPC-1 cells transduced with oe-GTF2I alone or combined with sh-FAT1-1 measured by Transwell assay. (D) Western blot analysis of EMT-related proteins Vimentin, slug, snail, E-cadherin, and N-cadherin in TPC-1 cells transduced with oe-GTF2I alone or combined with sh-FAT1-1. (E) Stemness maintenance in TPC-1 cells transduced with oe-GTF2I alone or combined with sh-FAT1-1 measured by sphere formation experiment. (F) Western blot analysis of stemness-related proteins CD133, Oct4, ALDH1A1, and c-Myc in TPC-1 cells transduced with oe-GTF2I alone or combined with sh-FAT1-1. **P < 0.01, ***P < 0.001, and ****P < 0.0001. The cell experiment was conducted three times independently.

Fig.4 GTF2I can be delivered to TPC-1 cells by MSC-EVs. (A) Morphological characterization of MSC-EVs observed under TEM. (B) Size distribution of MSC-EVs analyzed by NTA. (C) Western blot analysis of EV surface maker proteins CD9, CD63, TSG101, and calnexin in the isolated EVs. (D) Internalization of PKH67-labeled MSC-EVs by TPC-1 cells under a fluorescence microscope. (E) Entry of GFP-labeled GTF2I into TPC-1 cells via MSC-EVs. (F) Western blot analysis of GTF2I protein in TPC-1 cells treated with MSC-EVs or MSC-EVs + sh-GTF2I-1. **P < 0.01. The cell experiment was conducted three times independently.

Fig.5 MSC-EVs deliver GTF2I to TC cells where GTF2I inhibits the oncogenic phenotypes, EMT, and stemness maintenance of TC cells by increasing FAT1. (A) GTF2I and FAT1 expression in TPC-1 cells treated with MSC-EVs and MSC-EVs + sh-FAT1-1 determined by RT-qPCR and Western blot analysis. (B) Clonogenic potential of TPC-1 cells treated with MSC-EVs and MSC-EVs + sh-FAT1-1 measured by colony formation assay. (C) Migration and invasion of TPC-1 cells treated with MSC-EVs and MSC-EVs + sh-FAT1-1 measured by Transwell assay. (D) Western blot analysis of EMT-related proteins Vimentin, slug, snail, E-cadherin and N-cadherin in TPC-1 cells treated with MSC-EVs and MSC-EVs + sh-FAT1-1. (E) Stemness maintenance in TPC-1 cells treated with MSC-EVs and MSC-EVs + sh-FAT1-1 measured by sphere formation experiment. (F) Western blot analysis of stemness-related proteins CD133, Oct4, ALDH1A1, and c-Myc in TPC-1 cells treated with MSC-EVs and MSC-EVs + sh-FAT1-1. **P < 0.01, ***P < 0.001, and ****P < 0.0001. The cell experiment was conducted three times independently.

Fig.6 Inactivated CDK4/FOXM1 is responsible for the inhibiting effect of FAT1 on the oncogenic phenotypes, EMT, and stemness maintenance of TC cells. (A) Expression of CDK4 and FOXM1 in the normal samples (blue box; n = 58) and TC samples (yellow box; n = 510). (B) RT-qPCR detection of CDK4 and FOXM1 expression in TC tissues and adjacent tissues. (C) RT-qPCR detection of CDK4 and FOXM1 expression in TC cell lines (TPC-1, 8305C, CAL62, and IHH4) and normal thyroid cell line Nthy-ori 3-1. (D) RT-qPCR detection of FAT1, CDK4, and FOXM1 expression in TPC-1 cells treated with oe-FAT1 or oe-FAT1 + oe-CDK4. (E) Clonogenic potential of TPC-1 cells treated with oe-FAT1 or oe-FAT1 + oe-CDK4 measured by colony formation assay. (F) Migration and invasion of TPC-1 cells treated with oe-FAT1 or oe-FAT1 + oe-CDK4 measured by Transwell assay. (G) Western blot analysis of EMT-related proteins Vimentin, slug, snail, E-cadherin, and N-cadherin in TPC-1 cells treated with oe-FAT1 or oe-FAT1 + oe-CDK4. (H) Stemness maintenance in TPC-1 cells treated with oe-FAT1 or oe-FAT1 + oe-CDK4 measured by sphere formation experiment. (I) Western blot analysis of stemness-related proteins CD133, Oct4, ALDH1A1, and c-Myc in TPC-1 cells treated with oe-FAT1 or oe-FAT1 + oe-CDK4. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. The cell experiment was conducted three times independently.

Fig.7 GTF2I delivered by MSC-EVs upregulates FAT1 expression and inactivates CDK4/FOXM1, thereby impeding the malignant characteristics of TC cells. TPC-1 cells were treated with MSC-EVs/oe-NC, MSC-EVs/oe-GTF2I + oe-NC, and MSC-EVs/oe-GTF2I + oe-FOXM1. (A) Western blot analysis of GTF2I protein in TPC-1 cells. (B) RT-qPCR detection of FAT1, CDK4, and FOXM1 expression in TPC-1 cells. (C) Clonogenic potential of TPC-1 cells measured by colony formation assay. (D) Migration and invasion of TPC-1 cells measured by Transwell assay. (E) Western blot analysis of EMT-related proteins Vimentin, slug, snail, E-cadherin, and N-cadherin in TPC-1 cells. (F) Stemness maintenance in TPC-1 cells measured by sphere formation experiment. (G) Western blot analysis of stemness-related proteins CD133, Oct4, ALDH1A1, and c-Myc in TPC-1 cells. **P < 0.01, ***P < 0.001, and ****P < 0.0001. The cell experiment was conducted three times independently.

Fig.8 GTF2I delivered by MSC-EVs retards tumorigenesis of TC cells. (A) Tumor volume of mice treated with MSC-EVs and MSC-EVs/sh-GTF2I. (B) Representative images showing xenografts in mice treated with MSC-EVs and MSC-EVs/sh-GTF2I. (C) Quantitative analysis of xenograft tumor weight in nude mice treated with MSC-EVs and MSC-EVs/sh-GTF2I. (D) Western blot analysis of GTF2I protein in the tumor tissue of mice treated with MSC-EVs and MSC-EVs/sh-GTF2I. (E) RT-qPCR detection of FAT1, CDK4, and FOXM1 expression in the tumor tissue of mice treated with MSC-EVs and MSC-EVs/sh-GTF2I. (F) Ki67 staining of tumor growth in mice treated with MSC-EVs and MSC-EVs/sh-GTF2I. (G) HE staining of metastatic nodules in lung tissues of mice treated with MSC-EVs and MSC-EVs/sh-GTF2I. **P < 0.01, ***P < 0.001, and ****P < 0.0001. n = 6 mice for each treatment.

Fig.9 Schematic of the mechanism by which GTF2I-loaded MSC-EVs affect TC. MSC-EVs deliver GTF2I to TPC-1 cells, resulting in increased expression of FAT1 and downregulated CDK4/FOXM1, thereby suppressing the proliferation, migration, invasion, EMT, and stemness maintenance of TC cells.

1	F Bray, J Ferlay, I Soerjomataram, RL Siegel, LA Torre, A Jemal. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394–424 https://doi.org/10.3322/caac.21492
2	J Kim, JE Gosnell, SA Roman. Geographic influences in the global rise of thyroid cancer. Nat Rev Endocrinol 2020; 16(1): 17–29 https://doi.org/10.1038/s41574-019-0263-x
3	SN Aleksakhina, A Kashyap, EN Imyanitov. Mechanisms of acquired tumor drug resistance. Biochim Biophys Acta Rev Cancer 2019; 1872(2): 188310 https://doi.org/10.1016/j.bbcan.2019.188310
4	F Bocci, L Gearhart-Serna, M Boareto, M Ribeiro, E Ben-Jacob, GR Devi, H Levine, JN Onuchic, MK Jolly. Toward understanding cancer stem cell heterogeneity in the tumor microenvironment. Proc Natl Acad Sci USA 2019; 116(1): 148–157 https://doi.org/10.1073/pnas.1815345116
5	S Pai, OA Bamodu, YK Lin, CS Lin, PY Chu, MH Chien, LS Wang, M Hsiao, CT Yeh, JT Tsai. CD47-SIRPα signaling induces epithelial-mesenchymal transition and cancer stemness and links to a poor prognosis in patients with oral squamous cell carcinoma. Cells 2019; 8(12): 1658 https://doi.org/10.3390/cells8121658
6	Z Zhang, ZX Wang, YX Chen, HX Wu, L Yin, Q Zhao, HY Luo, ZL Zeng, MZ Qiu, RH Xu. Integrated analysis of single-cell and bulk RNA sequencing data reveals a pan-cancer stemness signature predicting immunotherapy response. Genome Med 2022; 14(1): 45 https://doi.org/10.1186/s13073-022-01050-w
7	MC Sanmartin, FR Borzone, MB Giorello, G Yannarelli, NA Chasseing. Mesenchymal stromal cell-derived extracellular vesicles as biological carriers for drug delivery in cancer therapy. Front Bioeng Biotechnol 2022; 10: 882545 https://doi.org/10.3389/fbioe.2022.882545
8	A Hassanzadeh, HS Rahman, A Markov, JJ Endjun, AO Zekiy, MS Chartrand, N Beheshtkhoo, MAJ Kouhbanani, F Marofi, M Nikoo, M Jarahian. Mesenchymal stem/stromal cell-derived exosomes in regenerative medicine and cancer; overview of development, challenges, and opportunities. Stem Cell Res Ther 2021; 12(1): 297 https://doi.org/10.1186/s13287-021-02378-7
9	S Rani, AE Ryan, MD Griffin, T Ritter. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Mol Ther 2015; 23(5): 812–823 https://doi.org/10.1038/mt.2015.44
10	G Qiu, G Zheng, M Ge, J Wang, R Huang, Q Shu, J Xu. Mesenchymal stem cell-derived extracellular vesicles affect disease outcomes via transfer of microRNAs. Stem Cell Res Ther 2018; 9(1): 320 https://doi.org/10.1186/s13287-018-1069-9
11	A Gurumurthy, Q Wu, R Nar, K Paulsen, A Trumbull, RC Fishman, M Brand, J Strouboulis, Z Qian, J Bungert. TFII-I/Gtf2i and erythro-megakaryopoiesis. Front Physiol 2020; 11: 590180 https://doi.org/10.3389/fphys.2020.590180
12	S Nathany, R Tripathi, A Mehta. Gene of the month: GTF2I. J Clin Pathol 2021; 74(1): 1–4 https://doi.org/10.1136/jclinpath-2020-207013
13	IK Kim, G Rao, X Zhao, R Fan, ML Avantaggiati, Y Wang, YW Zhang, G Giaccone. Mutant GTF2I induces cell transformation and metabolic alterations in thymic epithelial cells. Cell Death Differ 2020; 27(7): 2263–2279 https://doi.org/10.1038/s41418-020-0502-7
14	I Pastushenko, F Mauri, Y Song, Cock F de, B Meeusen, B Swedlund, F Impens, Haver D Van, M Opitz, M Thery, Y Bareche, G Lapouge, M Vermeersch, Eycke YR Van, C Balsat, C Decaestecker, Y Sokolow, S Hassid, A Perez-Bustillo, B Agreda-Moreno, L Rios-Buceta, P Jaen, P Redondo, R Sieira-Gil, JF Millan-Cayetano, O Sanmatrtin, N D’Haene, V Moers, M Rozzi, J Blondeau, S Lemaire, S Scozzaro, V Janssens, Troya M De, C Dubois, D Pérez-Morga, I Salmon, C Sotiriou, F Helmbacher, C Blanpain. Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis. Nature 2021; 589(7842): 448–455 https://doi.org/10.1038/s41586-020-03046-1
15	N Qu, X Shi, JJ Zhao, H Guan, TT Zhang, SS Wen, T Liao, JQ Hu, WY Liu, YL Wang, S Huang, RL Shi, Y Wang, QH Ji. Genomic and transcriptomic characterization of sporadic medullary thyroid carcinoma. Thyroid 2020; 30(7): 1025–1036 https://doi.org/10.1089/thy.2019.0531
16	Z Li, P Razavi, Q Li, W Toy, B Liu, C Ping, W Hsieh, F Sanchez-Vega, DN Brown, AF Da Cruz Paula, L Morris, P Selenica, E Eichenberger, R Shen, N Schultz, N Rosen, M Scaltriti, E Brogi, J Baselga, JS Reis-Filho, S Chandarlapaty. Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the hippo pathway. Cancer Cell 2018; 34(6): 893–905.e8 https://doi.org/10.1016/j.ccell.2018.11.006
17	X Wang, Z Sun, W Tian, C Piao, X Xie, J Zang, S Peng, X Yu, Y Wang. S100A12 is a promising biomarker in papillary thyroid cancer. Sci Rep 2020; 10(1): 1724 https://doi.org/10.1038/s41598-020-58534-1
18	C Rubio, M Martínez-Fernández, C Segovia, I Lodewijk, C Suarez-Cabrera, C Segrelles, F López-Calderón, E Munera-Maravilla, M Santos, A Bernardini, R García-Escudero, C Lorz, MJ Gómez-Rodriguez, Velasco G de, I Otero, F Villacampa, F Guerrero-Ramos, S Ruiz, la Rosa F de, S Domínguez-Rodríguez, FX Real, N Malats, D Castellano, M Dueñas, JM Paramio. CDK4/6 inhibitor as a novel therapeutic approach for advanced bladder cancer independently of RB1 status. Clin Cancer Res 2019; 25(1): 390–402 https://doi.org/10.1158/1078-0432.CCR-18-0685
19	R Bellelli, MD Castellone, G Garcia-Rostan, C Ugolini, C Nucera, PM Sadow, TC Nappi, P Salerno, MC Cantisani, F Basolo, TA Gago, G Salvatore, M Santoro. FOXM1 is a molecular determinant of the mitogenic and invasive phenotype of anaplastic thyroid carcinoma. Endocr Relat Cancer 2012; 19(5): 695–710 https://doi.org/10.1530/ERC-12-0031
20	L Feng, B Yang, XD Tang. Long noncoding RNA LINC00460 promotes carcinogenesis via sponging miR-613 in papillary thyroid carcinoma. J Cell Physiol 2019; 234(7): 11431–11439 https://doi.org/10.1002/jcp.27799
21	F Xia, Y Chen, B Jiang, X Du, Y Peng, W Wang, W Huang, T Feng, X Li. Long noncoding RNA HOXA-AS2 promotes papillary thyroid cancer progression by regulating miR-520c-3p/S100A4 pathway. Cell Physiol Biochem 2018; 50(5): 1659–1672 https://doi.org/10.1159/000494786
22	Z Liao, R Luo, G Li, Y Song, S Zhan, K Zhao, W Hua, Y Zhang, X Wu, C Yang. Exosomes from mesenchymal stem cells modulate endoplasmic reticulum stress to protect against nucleus pulposus cell death and ameliorate intervertebral disc degeneration in vivo. Theranostics 2019; 9(14): 4084–4100 https://doi.org/10.7150/thno.33638
23	A Pritchard, S Tousif, Y Wang, K Hough, S Khan, J Strenkowski, BK Chacko, VM Darley-Usmar, JS Deshane. Lung tumor cell-derived exosomes promote M2 macrophage polarization. Cells 2020; 9(5): 1303 https://doi.org/10.3390/cells9051303
24	T Fang, H Lv, G Lv, T Li, C Wang, Q Han, L Yu, B Su, L Guo, S Huang, D Cao, L Tang, S Tang, M Wu, W Yang, H Wang. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun 2018; 9(1): 191 https://doi.org/10.1038/s41467-017-02583-0
25	XJ Shao, SF Xiang, YQ Chen, N Zhang, J Cao, H Zhu, B Yang, Q Zhou, MD Ying, QJ He. Inhibition of M2-like macrophages by all-trans retinoic acid prevents cancer initiation and stemness in osteosarcoma cells. Acta Pharmacol Sin 2019; 40(10): 1343–1350 https://doi.org/10.1038/s41401-019-0262-4
26	X Dai, Y Xie, M Dong. Cancer-associated fibroblasts derived extracellular vesicles promote angiogenesis of colorectal adenocarcinoma cells through miR-135b-5p/FOXO1 axis. Cancer Biol Ther 2022; 23(1): 76–88 https://doi.org/10.1080/15384047.2021.2017222
27	Y Yang, F Mao, L Guo, J Shi, M Wu, S Cheng, W Guo. Tumor cells derived-extracellular vesicles transfer miR-3129 to promote hepatocellular carcinoma metastasis by targeting TXNIP. Dig Liver Dis 2021; 53(4): 474–485 https://doi.org/10.1016/j.dld.2021.01.003
28	Y Cui, D Wang, M Xie. Tumor-derived extracellular vesicles promote activation of carcinoma-associated fibroblasts and facilitate invasion and metastasis of ovarian cancer by carrying miR-630. Front Cell Dev Biol 2021; 9: 652322 https://doi.org/10.3389/fcell.2021.652322
29	XZ Yang, TT Cheng, QJ He, ZY Lei, J Chi, Z Tang, QX Liao, H Zhang, LS Zeng, SZ Cui. LINC01133 as ceRNA inhibits gastric cancer progression by sponging miR-106a-3p to regulate APC expression and the Wnt/β-catenin pathway. Mol Cancer 2018; 17(1): 126 https://doi.org/10.1186/s12943-018-0874-1
30	C Wei, C Yang, S Wang, D Shi, C Zhang, X Lin, Q Liu, R Dou, B Xiong. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer 2019; 18(1): 64 https://doi.org/10.1186/s12943-019-0976-4
31	H Liang, T Yu, Y Han, H Jiang, C Wang, T You, X Zhao, H Shan, R Yang, L Yang, H Shan, Y Gu. LncRNA PTAR promotes EMT and invasion-metastasis in serous ovarian cancer by competitively binding miR-101-3p to regulate ZEB1 expression. Mol Cancer 2018; 17(1): 119 https://doi.org/10.1186/s12943-018-0870-5
32	KS Park, E Bandeira, GV Shelke, C Lässer, J Lötvall. Enhancement of therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res Ther 2019; 10(1): 288 https://doi.org/10.1186/s13287-019-1398-3
33	Y Wang, G Wang, Y Ma, J Teng, Y Wang, Y Cui, Y Dong, S Shao, Q Zhan, X Liu. FAT1, a direct transcriptional target of E2F1, suppresses cell proliferation, migration and invasion in esophageal squamous cell carcinoma. Chin J Cancer Res 2019; 31(4): 609–619 https://doi.org/10.21147/j.issn.1000-9604.2019.04.05
34	SW Zhou, BB Su, YQ Feng, XQ Du, H Zhao. Expression of GTF2IP23 in breast cancer and it mediated regulation of GTF2I. Chin J Oncol (Zhonghua Zhong Liu Za Zhi) 2019; 41(12): 918–922
35	Y Chen, Z Shao, E Jiang, X Zhou, L Wang, H Wang, X Luo, Q Chen, K Liu, Z Shang. CCL21/CCR7 interaction promotes EMT and enhances the stemness of OSCC via a JAK2/STAT3 signaling pathway. J Cell Physiol 2020; 235(9): 5995–6009 https://doi.org/10.1002/jcp.29525
36	Z Xunian, R Kalluri. Biology and therapeutic potential of mesenchymal stem cell-derived exosomes. Cancer Sci 2020; 111(9): 3100–3110 https://doi.org/10.1111/cas.14563
37	M Tang, Q Wang, K Wang, F Wang. Mesenchymal stem cells-originated exosomal microRNA-152 impairs proliferation, invasion and migration of thyroid carcinoma cells by interacting with DPP4. J Endocrinol Invest 2020; 43(12): 1787–1796 https://doi.org/10.1007/s40618-020-01406-2
38	XL Hu, YF Zhai, GD Li, JF Xing, J Yang, YH Bi, J Wang, RY Shi. FAT1 inhibits cell proliferation of esophageal squamous cell carcinoma through regulating the expression of CDK4/CDK6/CCND1 complex. Zhonghua Zhong Liu Za Zhi 2018; 40(1): 14–20
39	L Anders, N Ke, P Hydbring, YJ Choi, HR Widlund, JM Chick, H Zhai, M Vidal, SP Gygi, P Braun, P Sicinski. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 2011; 20(5): 620–634 https://doi.org/10.1016/j.ccr.2011.10.001
40	S Lopes-Ventura, M Pojo, AT Matias, MM Moura, IJ Marques, V Leite, BM Cavaco. The efficacy of HRAS and CDK4/6 inhibitors in anaplastic thyroid cancer cell lines. J Endocrinol Invest 2019; 42(5): 527–540 https://doi.org/10.1007/s40618-018-0947-4
41	G Wang, X Wang, Y Jin. LINC01410/miR-3619-5p/FOXM1 Feedback Loop Regulates Papillary Thyroid Carcinoma Cell Proliferation and Apoptosis. Cancer Biother Radiopharm 2019; 34(9): 572–580 https://doi.org/10.1089/cbr.2019.2854

[1]	FMD-23018-CJH-supplementary figures	Download
[2]		Download
[3]		Download
[4]		Download
[5]		Download

[1]	Kosar Babaei, Mohsen Aziminezhad, Seyedeh Elham Norollahi, Sogand Vahidi, Ali Akbar Samadani. Cell therapy for the treatment of reproductive diseases and infertility: an overview from the mechanism to the clinic alongside diagnostic methods[J]. Front. Med., 2022, 16(6): 827-858.
[2]	Xin Yin, Azhar Anwar, Yanbo Wang, Huanhuan Hu, Gaoli Liang, Chenyu Zhang. Paternal environmental exposure-induced spermatozoal small noncoding RNA alteration meditates the intergenerational epigenetic inheritance of multiple diseases[J]. Front. Med., 2022, 16(2): 176-184.
[3]	Lingling Tang, Yingan Jiang, Mengfei Zhu, Lijun Chen, Xiaoyang Zhou, Chenliang Zhou, Peng Ye, Xiaobei Chen, Baohong Wang, Zhenyu Xu, Qiang Zhang, Xiaowei Xu, Hainv Gao, Xiaojun Wu, Dong Li, Wanli Jiang, Jingjing Qu, Charlie Xiang, Lanjuan Li. Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19[J]. Front. Med., 2020, 14(5): 664-673.
[4]	Shihua Wang, Rongjia Zhu, Hongling Li, Jing Li, Qin Han, Robert Chunhua Zhao. Mesenchymal stem cells and immune disorders: from basic science to clinical transition[J]. Front. Med., 2019, 13(2): 138-151.
[5]	Yingchen Li,Guoheng Hu,Qilai Cheng. Implantation of human umbilical cord mesenchymal stem cells for ischemic stroke: perspectives and challenges[J]. Front. Med., 2015, 9(1): 20-29.
[6]	Lizhe Ai, Yaqin Yu, Xiaoli Liu, Chong Wang, Jieping Shi, Hui Sun, Qiong Yu. Are the SNPs of NKX2-1 associated with papillary thyroid carcinoma in the Han population of Northern China?[J]. Front Med, 2014, 8(1): 113-117.
[7]	Siming Yang, Kui Ma, Changjiang Feng, Yan Wu, Yao Wang, Sha Huang, Xiaobing Fu. Capacity of human umbilical cord-derived mesenchymal stem cells to differentiate into sweat gland-like cells: a preclinical study[J]. Front Med, 2013, 7(3): 345-353.
[8]	Siming Yang, Sha Huang, Changjiang Feng, Xiaobing Fu. Umbilical cord-derived mesenchymal stem cells: strategies, challenges, and potential for cutaneous regeneration[J]. Front Med, 2012, 6(1): 41-47.
[9]	Shihua Wang, Xuebin Qu, Robert Chunhua Zhao. Mesenchymal stem cells hold promise for regenerative medicine[J]. Front Med, 2011, 5(4): 372-378.
[10]	Li LI, Jianxin JIANG. Regulatory factors of mesenchymal stem cell migration into injured tissues and their signal transduction mechanisms[J]. Front Med, 2011, 5(1): 33-39.

Viewed

Full text

Abstract

Cited

Shared

Discussed