叉头转录因子家族在肝细胞癌中的作用机制及其作为治疗靶点的前景

李恬雨; 闫会敏

doi:10.3969/j.issn.1001-5256.2021.04.044

叉头转录因子家族在肝细胞癌中的作用机制及其作为治疗靶点的前景

DOI: 10.3969/j.issn.1001-5256.2021.04.044

李恬雨¹,
闫会敏^{1, 2, ,}

1.
河北医科大学公共卫生学院流行病与卫生统计学教研室，石家庄 050017
2.
石家庄市第五医院研究所，石家庄 050021

基金项目:

河北省医学适用技术跟踪项目 (GZ2020071)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：李恬雨负责资料分析，撰写及修改论文；闫会敏负责拟定写作思路，修改论文并最后定稿。

详细信息

作者简介:
李恬雨(1994—)，女，主要从事肝癌相关基因组学研究

通信作者:
闫会敏，yanhm_2538@163.com

中图分类号: R735.7
计量
- 文章访问数: 397
- HTML全文浏览量: 154
- PDF下载量: 31
- 被引次数: 0
出版历程
- 收稿日期: 2020-09-18
- 录用日期: 2020-11-05
- 出版日期: 2021-04-20

Mechanism of action of forkhead box transcription factors in hepatocellular carcinoma and their prospects as treatment targets

Tianyu LI¹,
Huimin YAN^{1, 2
, ,}

1.
Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China
2.
Clinical Research Center, Shijiazhuang Fifth Hospital, Shijiazhuang 050021, China

摘要

摘要: 肝细胞癌(HCC)是最常见的恶性癌症之一，发病率和病死率一直居高不下，预后很差。叉头框(FOX)转录因子家族可调控细胞的生长、分化及组织发育，在肿瘤中具有重要的生物学作用。综述了FOX家族分子表达与HCC发生发展及预后的关系，分析了FOX在HCC进展中发挥作用的机制，提出FOX家族分子有望成为HCC治疗的新靶点。
- 癌, 肝细胞 /
- 叉头转录因子类 /
- 癌基因 /
- 基因, 肿瘤抑制
Abstract: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers and has high incidence and mortality rates and poor prognosis. Forkhead box (FOX) transcription factor family can regulate cell growth, differentiation, and tissue development and plays an important role in tumor. This article reviews the association of the molecular expression of the FOX family with the development, progression, and prognosis of HCC and analyzes the mechanism of action of FOX in the progression of HCC. It is pointed out that FOX family is expected to become a new target for HCC treatment.
- Carcinoma, Hepatocellular /
- Forkhead Transcription Factors /
- Oncogenes /
- Genes, Tumor Suppressor

HTML全文

参考文献(45)

[1]	YUAN Z, YE M, QIE J, et al. FOXA1 promotes cell proliferation and suppresses apoptosis in HCC by directly regulating miR-212-3p/FOXA1/AGR2 signaling pathway[J]. Onco Targets Ther, 2020, 13: 5231-5240. DOI: 10.2147/OTT.S252890
[2]	WANG Y, YANG L, CHEN T, et al. A novel lncRNA MCM3AP-AS1 promotes the growth of hepatocellular carcinoma by targeting miR-194-5p/FOXA1 axis[J]. Mol Cancer, 2019, 18(1): 28. DOI: 10.1186/s12943-019-0957-7
[3]	LIU J, YU Z, XIAO Y, et al. Coordination of FOXA2 and SIRT6 suppresses the hepatocellular carcinoma progression through ZEB2 inhibition[J]. Cancer Manag Res, 2018, 10: 391-402. DOI: 10.2147/CMAR.S150552
[4]	WANG LB, WANG X, CAO J, et al. Inhibitory effect of FOXA2 on proliferation and tumorigenesis of hepatocellular carcinoma cells[J]. J Pract Med, 2019, 35(4): 546-551. (in Chinese) DOI: 10.3969/j.issn.1006-5725.2019.04.010 王立斌, 王曦, 曹佳, 等. 叉头框蛋白A2对肝癌细胞增殖和成瘤的抑制作用[J]. 实用医学杂志, 2019, 35(4): 546-551. DOI: 10.3969/j.issn.1006-5725.2019.04.010
[5]	LIANG WC, REN JL, WONG CW, et al. LncRNA-NEF antagonized epithelial to mesenchymal transition and cancer metastasis via cis-regulating FOXA2 and inactivating Wnt/β-catenin signaling[J]. Oncogene, 2018, 37(11): 1445-1456. DOI: 10.1038/s41388-017-0041-y
[6]	LI Z, TUTEJA G, SCHUG J, et al. Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer[J]. Cell, 2012, 148(1-2): 72-83. DOI: 10.1016/j.cell.2011.11.026
[7]	TAKASHIMA Y, HORISAWA K, UDONO M, et al. Prolonged inhibition of hepatocellular carcinoma cell proliferation by combinatorial expression of defined transcription factors[J]. Cancer Sci, 2018, 109(11): 3543-3553. DOI: 10.1111/cas.13798
[8]	CHENG Z, HE Z, CAI Y, et al. Conversion of hepatoma cells to hepatocyte-like cells by defined hepatocyte nuclear factors[J]. Cell Res, 2019, 29(2): 124-135. DOI: 10.1038/s41422-018-0111-x
[9]	XIA L, HUANG W, TIAN D, et al. Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma[J]. Hepatology, 2013, 57(2): 610-624. DOI: 10.1002/hep.26029
[10]	HUANG W, CHEN Z, ZHANG L, et al. Interleukin-8 induces expression of FOXC1 to promote transactivation of CXCR1 and CCL2 in hepatocellular carcinoma cell lines and formation of metastases in mice[J]. Gastroenterology, 2015, 149(4): 1053-1067.e14. DOI: 10.1053/j.gastro.2015.05.058
[11]	SHIMODA Y, UBUKATA Y, HANDA T, et al. High expression of forkhead box protein C2 is associated with aggressive phenotypes and poor prognosis in clinical hepatocellular carcinoma[J]. BMC Cancer, 2018, 18(1): 597. DOI: 10.1186/s12885-018-4503-6
[12]	LIANG C, ZHAO J, GE H, et al. Clinicopathological and prognostic significance of FoxM1 in hepatocellular carcinoma patients: A meta-analysis[J]. Onco Targets Ther, 2018, 11: 3561-3571. DOI: 10.2147/OTT.S155541
[13]	KOPANJA D, PANDEY A, KIEFER M, et al. Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features[J]. J Hepatol, 2015, 63(2): 429-436. DOI: 10.1016/j.jhep.2015.03.023
[14]	FILLIOL A, SCHWABE RF. FoxM1 induces CCl₂ secretion from hepatocytes triggering hepatic inflammation, injury, fibrosis, and liver cancer[J]. Cell Mol Gastroenterol Hepatol, 2020, 9(3): 555-556. DOI: 10.1016/j.jcmgh.2020.01.002
[15]	LI Y, LU L, TU J, et al. Reciprocal regulation between forkhead box M1/NF-κB and methionine adenosyltransferase 1a drives liver cancer[J]. Hepatology, 2020, 72(5): 1682-1700. DOI: 10.1002/hep.31196
[16]	HU G, YAN Z, ZHANG C, et al. FOXM1 promotes hepatocellular carcinoma progression by regulating KIF4A expression[J]. J Exp Clin Cancer Res, 2019, 38(1): 188. DOI: 10.1186/s13046-019-1202-3
[17]	WANG Y, WANG H, YAN Z, et al. The critical role of dysregulated Hh-FOXM1-TPX2 signaling in human hepatocellular carcinoma cell proliferation[J]. Cell Commun Signal, 2020, 18(1): 116. DOI: 10.1186/s12964-020-00628-4
[18]	SHANG R, WANG M, DAI B, et al. Long noncoding RNA SLC2A1-AS1 regulates aerobic glycolysis and progression in hepatocellular carcinoma via inhibiting the STAT3/FOXM1/GLUT1 pathway[J]. Mol Oncol, 2020, 14(6): 1381-1396. DOI: 10.1002/1878-0261.12666
[19]	LIU S, QIU J, HE G, et al. LncRNA MALAT1 acts as a miR-125a-3p sponge to regulate FOXM1 expression and promote hepatocellular carcinoma progression[J]. J Cancer, 2019, 10(26): 6649-6659. DOI: 10.7150/jca.29213
[20]	WEI Y, WANG Z, ZONG Y, et al. LncRNA MFI2-AS1 promotes HCC progression and metastasis by acting as a competing endogenous RNA of miR-134 to upregulate FOXM1 expression[J]. Biomed Pharmacother, 2020, 125: 109890. DOI: 10.1016/j.biopha.2020.109890
[21]	SHI H, FANG R, LI Y, et al. The oncoprotein HBXIP suppresses gluconeogenesis through modulating PCK1 to enhance the growth of hepatoma cells[J]. Cancer Lett, 2016, 382(2): 147-156. DOI: 10.1016/j.canlet.2016.08.025
[22]	JIANG J, LIU Z, GE C, et al. NK3 homeobox 1 (NKX3.1) up-regulates forkhead box O1 expression in hepatocellular carcinoma and thereby suppresses tumor proliferation and invasion[J]. J Biol Chem, 2017, 292(47): 19146-19159. DOI: 10.1074/jbc.M117.793760
[23]	LIN X, ZUO S, LUO R, et al. HBX-induced miR-5188 impairs FOXO1 to stimulate β-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma[J]. Theranostics, 2019, 9(25): 7583-7598. DOI: 10.7150/thno.37717
[24]	LU M, HARTMANN D, BRAREN R, et al. Oncogenic Akt-FOXO3 loop favors tumor-promoting modes and enhances oxidative damage-associated hepatocellular carcinogenesis[J]. BMC Cancer, 2019, 19(1): 887. DOI: 10.1186/s12885-019-6110-6
[25]	WANG H, ZHANG CZ, LU SX, et al. A coiled-coil domain containing 50 splice variant is modulated by serine/arginine-rich splicing factor 3 and promotes hepatocellular carcinoma in mice by the ras signaling pathway[J]. Hepatology, 2019, 69(1): 179-195. DOI: 10.1002/hep.30147
[26]	GONG C, AI J, FAN Y, et al. NCAPG promotes the proliferation of hepatocellular carcinoma through PI3K/AKT signaling[J]. Onco Targets Ther, 2019, 12: 8537-8552. DOI: 10.2147/OTT.S217916
[27]	YU X, GAO X, MAO X, et al. Knockdown of FOXO6 inhibits glycolysis and reduces cell resistance to paclitaxel in HCC cells via PI3K/Akt signaling pathway[J]. Onco Targets Ther, 2020, 13: 1545-1556. DOI: 10.2147/OTT.S233031
[28]	WANG X, SUN J, CUI M, et al. Downregulation of FOXP1 inhibits cell proliferation in hepatocellular carcinoma by inducing G1/S phase cell cycle arrest[J]. Int J Mol Sci, 2016, 17(9): 1501. DOI: 10.3390/ijms17091501
[29]	YAN X, ZHOU H, ZHANG T, et al. Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion[J]. Tumour Biol, 2015, 36(12): 9611-9619. DOI: 10.1007/s13277-015-3701-y
[30]	XIAO WL. Mechanism of regularatory T cells in tumor immunity and the new strategy of treatment[J]. Chin J Cancer Biother, 2019, 26(12): 1387-1391. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-ZLSW201912015.htm 肖文路. 调节性T细胞在肿瘤免疫中作用机制及治疗新策略的研究进展[J]. 中国肿瘤生物治疗杂志, 2019, 26(12): 1387-1391. https://www.cnki.com.cn/Article/CJFDTOTAL-ZLSW201912015.htm
[31]	SHI JY, MA LJ, ZHANG JW, et al. FOXP3 is a HCC suppressor gene and acts through regulating the TGF-β/Smad2/3 signaling pathway[J]. BMC Cancer, 2017, 17(1): 648. DOI: 10.1186/s12885-017-3633-6
[32]	ZHANG G, ZHANG G. Upregulation of FoxP4 in HCC promotes migration and invasion through regulation of EMT[J]. Oncol Lett, 2019, 17(4): 3944-3951. http://www.ncbi.nlm.nih.gov/pubmed/30930991
[33]	ZHAO ZG, WANG DQ, HU DF, et al. Decreased FOXF1 promotes hepatocellular carcinoma tumorigenesis, invasion, and stemness and is associated with poor clinical outcome[J]. Onco Targets Ther, 2016, 9: 1743-1752. http://www.ncbi.nlm.nih.gov/pubmed/27042124
[34]	SHI Z, LIU J, YU X, et al. Loss of FOXF2 expression predicts poor prognosis in hepatocellular carcinoma patients[J]. Ann Surg Oncol, 2016, 23(1): 211-217. DOI: 10.1245/s10434-015-4515-2
[35]	ZHENG X, LIN J, WU H, et al. Forkhead box (FOX) G1 promotes hepatocellular carcinoma epithelial-Mesenchymal transition by activating Wnt signal through forming T-cell factor-4/Beta-catenin/FOXG1 complex[J]. J Exp Clin Cancer Res, 2019, 38(1): 475. DOI: 10.1186/s13046-019-1433-3
[36]	ZHU X, LI ZG, YANG YZ, et al. Levels of FOXJ1 and NF-κB in hepatocellular carcinoma and its clinical significance[J]. Chin J Health Lab Technol, 2019, 29(15): 1863-1866. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-ZWJZ201915022.htm 朱侠, 李治刚, 杨永志, 等. 叉头框转录因子J和核转录因子κB在肝细胞肝癌中的表达及其临床意义[J]. 中国卫生检验杂志, 2019, 29(15): 1863-1866. https://www.cnki.com.cn/Article/CJFDTOTAL-ZWJZ201915022.htm
[37]	JIN GZ, ZHANG Y, CONG WM, et al. Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking[J]. PLoS Biol, 2018, 16(10): e2006483. DOI: 10.1371/journal.pbio.2006483
[38]	CAO H, CHU X, WANG Z, et al. High FOXK1 expression correlates with poor outcomes in hepatocellular carcinoma and regulates stemness of hepatocellular carcinoma cells[J]. Life Sci, 2019, 228: 128-134. DOI: 10.1016/j.lfs.2019.04.068
[39]	LIN MF, YANG YF, PENG ZP, et al. FOXK2, regulted by miR-1271-5p, promotes cell growth and indicates unfavorable prognosis in hepatocellular carcinoma[J]. Int J Biochem Cell Biol, 2017, 88: 155-161. DOI: 10.1016/j.biocel.2017.05.019
[40]	LEE HA, CHU KB, MOON EK, et al. Sensitization to oxidative stress and G2/M cell cycle arrest by histone deacetylase inhibition in hepatocellular carcinoma cells[J]. Free Radic Biol Med, 2020, 147: 129-138. DOI: 10.1016/j.freeradbiomed.2019.12.021
[41]	EGAWA M, YOSHIDA Y, OGURA S, et al. Increased expression of Forkhead box M1 transcription factor is associated with clinicopathological features and confers a poor prognosis in human hepatocellular carcinoma[J]. Hepatol Res, 2017, 47(11): 1196-1205. DOI: 10.1111/hepr.12854
[42]	GARTEL AL. A new target for proteasome inhibitors: FoxM1[J]. Expert Opin Investig Drugs, 2010, 19(2): 235-242. DOI: 10.1517/13543780903563364
[43]	HE L, YANG X, CAO X, et al. Casticin induces growth suppression and cell cycle arrest through activation of FOXO3a in hepatocellular carcinoma[J]. Oncol Rep, 2013, 29(1): 103-108. DOI: 10.3892/or.2012.2076
[44]	WANG JG, ZHENG XX, ZENG GY, et al. Purified vitexin compound 1 induces apoptosis through activation of FOXO3a in hepatocellular carcinoma[J]. Oncol Rep, 2014, 31(1): 488-496. DOI: 10.3892/or.2013.2855
[45]	JIANG J, HUANG Z, CHEN X, et al. Trifluoperazine activates FOXO1-related signals to inhibit tumor growth in hepatocellular carcinoma[J]. DNA Cell Biol, 2017, 36(10): 813-821. DOI: 10.1089/dna.2017.3790