The impact of FOXP2 mediated by the Hedgehog signaling pathway on glycolysis participating in the proliferation and metastasis in uterine leiomyoma cells

doi:10.3969/j.issn.1006-7795.2025.01.018

Abstract

Abstract: Objective To explore the role of forkhead box protein p2 (FOXP2) in the proliferation and metastasis of uterine fibroid cells by regulating glycolysis mediated by Hedgehog signaling pathway. Methods Fresh hysteromyoma tissue was obtained from 10 patients who underwent myomectomy in the Department of Gynecology of Guizhou Provincial Hospital of Workers, and hysteromyoma cells were digested and separated. Cells were transfected with lentivirus shRNA targeting FOXP2 (sh-FOXP2), negative control (sh-NC) and FOXP2 overexpression vectors (oe-FOXP2), and negative control (oe-NC). Colony formation test and Transwell assay were used to evaluate the cell proliferation and metastasis ability. Glucose uptake, lactic acid production and extracellular acidification rate (ECAR) were measured to detect the aerobic glycolysis ability of cells. A xenograft tumor model was established by up-regulating uterine leiomyoma cells with FOXP2 to explore the regulatory effect of FOXP2 in vivo. Results Compared with oe-NC group, the cell viability, colony number, migrating cell number, glucose uptake, lactic acid production and ECAR in oe-FOXP2 group decreased significantly (P<0.05). Compared with sh-NC group, the cell viability, colony number, migrating cell number, glucose uptake, lactic acid production and ECAR of uterine fibroids in sh-FOXP2#1 and sh-FOXP2#2 groups increased significantly (P<0.05). Compared with oe-NC+vector group, the number of colonies, migrating cells, glucose uptake, lactic acid production, ECAR, Shh and Gli proteins in oe-FOXP2+vector group decreased significantly (P<0.05). Compared with oe-FOXP2+vector group, the number of colonies, migrating cells, glucose uptake, lactic acid production, ECAR, Shh and Gli proteins in oe-FOXP2+SAG group were significantly increased (P<0.05). Compared with oe-NC group, the tumor weight, the proportion of Ki-67 positive cells and the proteins of Shh, Gli, GLUT1 and PGAM1 in oe-FOXP2 group decreased significantly (P<0.05). Compared with oe-FOXP2 group, the tumor weight, the proportion of Ki-67 positive cells and the proteins of Shh, Gli, GLUT1 and PGAM1 in oe-FOXP2+SAG group increased significantly (P<0.05). Conclusions FOXP2 participates in the proliferation and metastasis of uterine leiomyoma cells by regulating glycolysis mediated by Hedgehog signaling pathway.

Key words: forkhead box protein p2, Hedgehog signal pathway, glycolysis, uterine fibroids

CLC Number:

Yang Yan, Tian Ni, Long Ling, Jia Zhenxiang. The impact of FOXP2 mediated by the Hedgehog signaling pathway on glycolysis participating in the proliferation and metastasis in uterine leiomyoma cells[J]. Journal of Capital Medical University, 2025, 46(1): 115-124.

0
/ Save 0 / Recommend

Add to citation manager EndNote|Reference Manager|ProCite|BibTeX|RefWorks

URL: https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/10.3969/j.issn.1006-7795.2025.01.018

https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/Y2025/V46/I1/115

References

［1］ Yang Q W, Ciebiera M, Bariani M V, et al. Comprehensive review of uterine fibroids: developmental origin, pathogenesis, and treatment［J］. Endocr Rev, 2022, 43(4): 678－719.
［2］ Bhat A S, Singh N A, Rymbai E, et al. Importance of fibrosis in the pathogenesis of uterine leiomyoma and the promising anti-fibrotic effects of dipeptidyl peptidase-4 and fibroblast activation protein inhibitors in the treatment of uterine leiomyoma［J］. Reprod Sci, 2023, 30(5): 1383－1398.
［3］ Fedotova M, Barysheva E, Bushueva O. Pathways of hypoxia-inducible factor (HIF) in the orchestration of uterine fibroids development［J］. Life (Basel), 2023, 13(8): 1740.
［4］ Wang H, Liang Z, Gou Y, et al. FTO-dependent N(6)-methyladenosine regulates the progression of endometriosis via the ATG5/PKM2 axis［J］. Cell Signal, 2022: 110406.
［5］ Chen F, Byrd A L, Liu J P, et al. Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors［J］. Nat Commun, 2023, 14(1): 336.
［6］ Nong S J, Wang Z W, Wei Z Q, et al. HN1L promotes stem cell-like properties by regulating TGF-β signaling pathway through targeting FOXP2 in prostate cancer［J］. Cell Biol Int, 2022, 46(1): 83－95.
［7］ Xu P H, Zhang X, Cao J C, et al. The novel role of circular RNA ST3GAL6 on blocking gastric cancer malignant behaviours through autophagy regulated by the FOXP2/Met/mTOR axis［J］. Clin Transl Med, 2022, 12(1): e707.
［8］ Yan L J, Sun H H, Chen Y L, et al. FOXP2 suppresses the proliferation, invasion, and aerobic glycolysis of hepatocellular carcinoma cells by regulating the KDM5A/FBP1 axis［J］. Environ Toxicol, 2024, 39(1): 341－356.
［9］ Carbajo-García M C, Corachán A, Juárez-Barber E, et al. Integrative analysis of the DNA methylome and transcriptome in uterine leiomyoma shows altered regulation of genes involved in metabolism, proliferation, extracellular matrix, and vesicles［J］. J Pathol, 2022, 257(5): 663－673.
［10］ Ali M, Stone D, Laknaur A, et al. EZH2 activates Wnt/β-catenin signaling in human uterine fibroids, which is inhibited by the natural compound methyl jasmonate［J］. F S Sci, 2023, 4(3): 239－256.
［11］ Yao Y X, Li T A, Yu T T, et al. Hedgehog signal activates AMPK via smoothened to promote autophagy and lipid degradation in hepatocytes［J］. Biochem Cell Biol, 2023, 101(4): 284－293.
［12］ Yang F, Rodriguez-Blanco J, Long J, et al. A druggable UHRF1/DNMT1/GLI complex regulates sonic Hedgehog-dependent tumor growth［J］. Mol Cancer Res, 2022, 20(11): 1598－1610.
［13］ Yu Y H, Zhang H J, Yang F, et al. Curcumol, a major terpenoid from Curcumae Rhizoma, attenuates human uterine leiomyoma cell development via the p38MAPK/NF-κB pathway［J］. J Ethnopharmacol, 2023, 310: 116311.
［14］ Li Y G, Chen S H, Zhang X, et al. U2 small nuclear RNA auxiliary factor 2, transcriptionally activated by the transcription factor Dp-1/E2F transcription factor 1 complex, enhances the growth and aerobic glycolysis of leiomyosarcoma cells［J］. Bioengineered, 2022, 13(4): 10200－10212.
［15］ Cope B M, Traweek R S, Lazcano R, et al. Targeting the molecular and immunologic features of leiomyosarcoma［J］. Cancers (Basel), 2023, 15(7): 2099.
［16］ Chadha M, Huang P H. Proteomic and metabolomic profiling in soft tissue sarcomas［J］. Curr Treat Options Oncol, 2022, 23(1): 78－88.
［17］ Coñuecar R, Asela I, Rivera M, et al. DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibility［J］. iScience, 2023, 26(7): 107228.
［18］ Yang F B, Xiao Z S, Zhang S Z. FOXP2 regulates thyroid cancer cell proliferation and apoptosis via transcriptional activation of RPS6KA6［J］. Exp Ther Med, 2022, 23(6): 434.
［19］ Yi J N, Tan S Y, Zeng Y J, et al. Comprehensive analysis of prognostic and immune infiltrates for FOXPs transcription factors in human breast cancer［J］. Sci Rep, 2022, 12(1): 8896.
［20］ Liao P, Huang W H, Cao L, et al. Low expression of FOXP2 predicts poor survival and targets caspase-1 to inhibit cell pyroptosis in colorectal cancer［J］. J Cancer, 2022, 13(4): 1181－1192.
［21］ Liu L, Chen G, Chen T, et al. si-SNHG5-FOXF2 inhibits TGF-β1-induced fibrosis in human primary endometrial stromal cells by the Wnt/β-catenin signalling pathway［J］. Stem Cell Res Ther, 2020, 11(1): 479.
［22］ Zhi X F, Jiang S, Zhang J X, et al. Ubiquitin-specific peptidase 24 accelerates aerobic glycolysis and tumor progression in gastric carcinoma through stabilizing PLK1 to activate NOTCH1［J］. Cancer Sci, 2023, 114(8): 3087－3100.
［23］ Liu Y, Tang W T, Ren L, et al. Activation of miR-500a-3p/CDK6 axis suppresses aerobic glycolysis and colorectal cancer progression［J］. J Transl Med, 2022, 20(1): 106.
［24］ Pouysségur J, Marchiq I, Parks S K, et al. ‘Warburg effect' controls tumor growth, bacterial, viral infections and immunity—Genetic deconstruction and therapeutic perspectives［J］. Semin Cancer Biol, 2022, 86(Pt 2): 334－346.
［25］ Yu X, Li W G, Feng Y J, et al. The prognostic value of hedgehog signaling in bladder cancer by integrated bioinformatics［J］. Sci Rep, 2023, 13(1): 6241.
［26］ Garg C, Khan H, Kaur A, et al. Therapeutic implications of sonic hedgehog pathway in metabolic disorders: Novel target for effective treatment［J］. Pharmacol Res, 2022, 179: 106194.
［27］ Zhu T, Zheng J Y, Zhuo W, et al. ETV4 promotes breast cancer cell stemness by activating glycolysis and CXCR4-mediated sonic Hedgehog signaling［J］. Cell Death Discov, 2021, 7(1): 126.
［28］ Chang W, Chang Q, Lu H D, et al. MiR-221-3p facilitates thyroid cancer cell proliferation and inhibit apoptosis by targeting FOXP2 through hedgehog pathway［J］. Mol Biotechnol, 2022, 64(8): 919－927.

[1]	Wang Jing, Zhou Qiaoyun, Wang Muyu, Xiao Yu, Song Dongmei, Guo Yan, Xia Enlan, Li Tinchiu, Huang Xiaowu. Analysis of risk factors and establishment of a prediction model for endometrial cancer in postmenopausal bleeding [J]. Journal of Capital Medical University, 2025, 46(1): 143-149.
[2]	iang Yan, Zhao Xuanyu, Sui Feng. Identifying diagnostic gene biomarkers of moderate or severe endometriosis [J]. Journal of Capital Medical University, 2024, 45(2): 322-332.
[3]	Li Xue, Shi Zhongyue, Yang Zhiming, Pang Wenbo, Jin Mulan. Value about artificial intelligence-assisted liquid-based thin-layer cytology for cytology cervical cancer screening [J]. Journal of Capital Medical University, 2020, 41(3): 360-363.
[4]	Huang Wenyang, Zheng Xiaojuan, Jiang Ying, Wang Shuzhen. Analysis of features of atypical hyperplasia patients with postoperative pathologic upgrade [J]. Journal of Capital Medical University, 2019, 40(6): 846-850.
[5]	Wang Shuzhen, Liu Wenting, Huang Wenyang, Zhang Yang, Zheng Jing, Jiang Ying. Treatment options for patients with non-atypical endometrial hyperplasia [J]. Journal of Capital Medical University, 2019, 40(6): 863-867.
[6]	Ma Xulan, Xia Di, Wang Huixiao, Jiang Ziwen, Dai Yinmei. Effect of estrogen on the proliferation and nude mouse tumorigenicity of endometrial carcinoma cells by mediating the expression of HOTAIR [J]. Journal of Capital Medical University, 2019, 40(6): 894-900.
[7]	Zhang Xuefang, He Xin, Huang Wenyang, Li Weihua, Luo Mei, Zhang Yang, Wang Shuzhen. A Meta-analysis of the relationship between cervical high-risk HPV infection and vaginal microecology in Chinese women [J]. Journal of Capital Medical University, 2018, 39(6): 841-848.
[8]	Luo Mei, He Xin, Liu Jun, Zhang Xuefang, Zhang Jianxin, Wang Qiuxi, Wang Shuzhen, Diao Xiaoli, Qu Jiuxin. Prevalent HPV 16 and 18 infection and vaginal microbiota in initial screening women [J]. Journal of Capital Medical University, 2018, 39(6): 849-857.
[9]	Li Jinghua, Huang Wenyan, Zhang Rui, Ma Xuelian, Shi Congning, Li Wenjun, Feng Limin. Evaluation of the preoperative myometrial free margin (MFM) of type Ⅱ submucosal fibroids by transvaginal ultrasonography [J]. Journal of Capital Medical University, 2016, 37(4): 523-528.
[10]	Zhang Kaiju;Zhao Yanzhong;Shang Hongwei;Kong Lu;Zhang Yuxiang. Establishment of Animal Model of Human Cervical Cancer in BALB/c Nude Mice by Tumor Tissue Xenograft [J]. Journal of Capital Medical University, 2008, 29(5): 593-596.
[11]	Zhao Ying;Zhang Weiyuan;Jia Hongmei;Chen Wei. Changes in mRNA Expression of Estrogen Receptor Isoform α, β and Insulin-like Growth Factor- I in Uterine Leiomyoma [J]. Journal of Capital Medical University, 2008, 29(5): 619-621.
[12]	Yang Baojun;Liu Hui;Feng Limin;Xing Fengling;Wang Enjie. Analysis on Subsequent of 25 Cases with Cervical Intraepithelial Neoplasia, Microinvasive Carcinoma after Cold-knife Conization [J]. Journal of Capital Medical University, 2008, 29(5): 650-652.
[13]	Wen Qiaoying;Zhang Hongru. Diagnosis and Treatment of Cervical Polyp by Hysteroscopy [J]. Journal of Capital Medical University, 2006, 27(4): 539-540.
[14]	Long Di;Cheng Jiumei;Wang Haiou;Li Yunfei;Zhu Xian. A Comparison between Transabdominal and Laparoscopic Myomectomy [J]. Journal of Capital Medical University, 2005, 26(6): 752-754.
[15]	Yang Shuli;Wu Yumei;Kong Weimin;Deng Xiaohong. The Assessment of Different Therapies for Endometrial Carcinoma [J]. Journal of Capital Medical University, 2005, 26(5): 584-587.