Krüppel样因子4在肝细胞癌发生发展中的作用机制

孙菲; 苏维玮; 付艳华; 王经伟

doi:10.3969/j.issn.1001-5256.2021.10.041

Krüppel样因子4在肝细胞癌发生发展中的作用机制

DOI: 10.3969/j.issn.1001-5256.2021.10.041

山东大学齐鲁医院(青岛) 肝病科, 山东青岛 266035

基金项目:

山东大学齐鲁医院(青岛)青年项目基金 (QDKY2020QN17)

详细信息

通信作者:
王经伟，nvwangjingwei@126.com

中图分类号: R735.7
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- 文章访问数: 593
- HTML全文浏览量: 111
- PDF下载量: 34
- 被引次数: 0
出版历程
- 收稿日期: 2021-06-08
- 录用日期: 2021-07-06
- 出版日期: 2021-10-20

Mechanism of KLF4 in the development and progression of hepatocellular carcinoma

Department of Hepatology, Qilu Hospital(Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, China

Research funding:

Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University Youth Project Fund (QDKY2020QN17)

摘要

摘要: 肝细胞癌发生发展机制复杂，目前尚未完全阐明。KLF4又称为胃肠富集Krüppel样因子，具有抑癌和促癌的双重调节作用。KLF4在肝癌中发挥抑癌作用，介绍了KLF4在肝癌发展过程中的生物学功能及调控机制，研究KLF4在肝癌中作用机制有望为肝癌的靶向治疗和预后监测提供新思路。
- 癌, 肝细胞 /
- Kruppel样转录因子类 /
- 生物学功能 /
- 分子机制
Abstract: The pathogenesis of hepatocellular carcinoma is complex and has not been fully clarified. KLF4, also known as gut-enriched Kruppel-like factor (GKLF), plays the dual regulatory role of tumor suppressor and tumor promoter. KLF4 plays an anti-cancer role in liver cancer. This article introduces the biological function and regulatory mechanism of KLF4 in the progression of liver cancer, and research on the mechanism of action of KLF4 in liver cancer is expected to provide new ideas for targeted therapy and prognosis monitoring of liver cancer.
- Carcinoma, Hepatocellular /
- Kruppel-Like Transcription Factors /
- Biological Function /
- Molecular Mechanism

HTML全文

图 1 KLF4在肝癌中的作用机制

注: KLF4的表达受到DNA甲基化、microRNA、DNA损伤等因素调节。KLF4调控的下游靶基因介导了KLF4在肝癌细胞中的抑制作用。

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参考文献(43)

[1]	CHEN W, ZHENG R, BAADE PD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-132. DOI: 10.3322/caac.21338.
[2]	YANG X, ZHANG D, LIU S, et al. KLF4 suppresses the migration of hepatocellular carcinoma by transcriptionally upregulating monoglyceride lipase[J]. Am J Cancer Res, 2018, 8(6): 1019-1029.
[3]	YU W, ROY SK, MA Y, et al. Higher expression of SATB2 in hepatocellular carcinoma of African Americans determines more aggressive phenotypes than those of Caucasian Americans[J]. J Cell Mol Med, 2019, 23(12): 7999-8009. DOI: 10.1111/jcmm.14652.
[4]	YU AQ, DING Y, LI CL, et al. TALEN-induced disruption of Nanog expression results in reduced proliferation, invasiveness and migration, increased chemosensitivity and reversal of EMT in HepG2 cells[J]. Oncol Rep, 2016, 35(3): 1657-1663. DOI: 10.3892/or.2015.4483.
[5]	CHEN J, ZHANG L, MA S, et al. The aberrant expressions of MACC1, ZEB1, and KLF4 in hepatocellular carcinoma and their clinical significance[J]. Int J Clin Exp Pathol, 2019, 12(9): 3653-3661.
[6]	LIU Y, OLANREWAJU YO, ZHENG Y, et al. Structural basis for Klf4 recognition of methylated DNA[J]. Nucleic Acids Res, 2014, 42(8): 4859-4867. DOI: 10.1093/nar/gku134.
[7]	WEI D, KANAI M, HUANG S, et al. Emerging role of KLF4 in human gastrointestinal cancer[J]. Carcinogenesis, 2006, 27(1): 23-31. DOI: 10.1093/carcin/bgi243.
[8]	BAN Y, LIU Y, LI Y, et al. S-nitrosation impairs KLF4 activity and instigates endothelial dysfunction in pulmonary arterial hypertension[J]. Redox Biol, 2019, 21: 101099. DOI: 10.1016/j.redox.2019.101099.
[9]	EVANS PM, ZHANG W, CHEN X, et al. Kruppel-like factor 4 is acetylated by p300 and regulates gene transcription via modulation of histone acetylation[J]. J Biol Chem, 2007, 282(47): 33994-34002. DOI: 10.1074/jbc.M701847200.
[10]	KIM MO, KIM SH, CHO YY, et al. ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4[J]. Nat Struct Mol Biol, 2012, 19(3): 283-290. DOI: 10.1038/nsmb.2217.
[11]	YANG WT, ZHENG PS. Promoter hypermethylation of KLF4 inactivates its tumor suppressor function in cervical carcinogenesis[J]. PLoS One, 2014, 9(2): e88827. DOI: 10.1371/journal.pone.0088827.
[12]	DING B, LIU P, LIU W, et al. Emerging roles of Krüppel-like factor 4 in cancer and cancer stem cells[J]. Asian Pac J Cancer Prev, 2015, 16(9): 3629-3633. DOI: 10.7314/apjcp.2015.16.9.3629.
[13]	MA Z, CHEN Y, MIN L, et al. Augmented miR-10b expression associated with depressed expression of its target gene KLF4 involved in gastric carcinoma[J]. Int J Clin Exp Pathol, 2015, 8(5): 5071-5079.
[14]	TIAN Y, LUO A, CAI Y, et al. MicroRNA-10b promotes migration and invasion through KLF4 in human esophageal cancer cell lines[J]. J Biol Chem, 2010, 285(11): 7986-7994. DOI: 10.1074/jbc.M109.062877.
[15]	XU J, LYU B, XU F, et al. Dynamic down-regulation of Krüppel-like factor 4 in colorectal adenoma-carcinoma sequence[J]. J Cancer Res Clin Oncol, 2008, 134(8): 891-898. DOI: 10.1007/s00432-008-0353-y.
[16]	SHI M, CUI J, DU J, et al. A novel KLF4/LDHA signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer[J]. Clin Cancer Res, 2014, 20(16): 4370-4380. DOI: 10.1158/1078-0432.CCR-14-0186.
[17]	LIN ZS, CHU HC, YEN YC, et al. Correction: Krüppel-like factor 4, a tumor suppressor in hepatocellular carcinoma cells reverts epithelial mesenchymal transition by suppressing slug expression[J]. PLoS One, 2016, 11(4): e0154168. DOI: 10.1371/journal.pone.0154168.
[18]	TIAN C, YAO S, LIU L, et al. Klf4 inhibits tumor growth and metastasis by targeting microRNA-31 in human hepatocellular carcinoma[J]. Int J Mol Med, 2017, 39(1): 47-56. DOI: 10.3892/ijmm.2016.2812.
[19]	SUN H, TANG H, XIE D, et al. Krüppel-like factor 4 blocks hepatocellular carcinoma dedifferentiation and progression through activation of hepatocyte nuclear factor-6[J]. Clin Cancer Res, 2016, 22(2): 502-512. DOI: 10.1158/1078-0432.CCR-15-0528.
[20]	NARANJO GÓMEZ JM, BERNAL JF, ARRANZ PG, et al. Alterations in the expression of p53, KLF4, and p21 in neuroendocrine lung tumors[J]. Arch Pathol Lab Med, 2014, 138(7): 936-942. DOI: 10.5858/arpa.2013-0119-OA.
[21]	LI L, YU S, WU Q, et al. KLF4-mediated CDH3 upregulation suppresses human hepatoma cell growth and migration via GSK-3β signaling[J]. Int J Biol Sci, 2019, 15(5): 953-961. DOI: 10.7150/ijbs.30857.
[22]	LI Q, GAO Y, JIA Z, et al. Dysregulated Krüppel-like factor 4 and vitamin D receptor signaling contribute to progression of hepatocellular carcinoma[J]. Gastroenterology, 2012, 143(3): 799-810. e2. DOI: 10.1053/j.gastro.2012.05.043.
[23]	LI Y, YU S, LI L, et al. KLF4-mediated upregulation of CD9 and CD81 suppresses hepatocellular carcinoma development via JNK signaling[J]. Cell Death Dis, 2020, 11(4): 299. DOI: 10.1038/s41419-020-2479-z.
[24]	CHAO J, ZHAO S, SUN H. Dedifferentiation of hepatocellular carcinoma: Molecular mechanisms and therapeutic implications[J]. Am J Transl Res, 2020, 12(5): 2099-2109.
[25]	HUJIE G, ZHOU SH, ZHANG H, et al. MicroRNA-10b regulates epithelial-mesenchymal transition by modulating KLF4/KLF11/Smads in hepatocellular carcinoma[J]. Cancer Cell Int, 2018, 18: 10. DOI: 10.1186/s12935-018-0508-0.
[26]	SUN H, PENG Z, TANG H, et al. Loss of KLF4 and consequential downregulation of Smad7 exacerbate oncogenic TGF-β signaling in and promote progression of hepatocellular carcinoma[J]. Oncogene, 2017, 36(21): 2957-2968. DOI: 10.1038/onc.2016.447.
[27]	LI XM, KIM SJ, HONG DK, et al. KLF4 suppresses the tumor activity of cutaneous squamous cell carcinoma (SCC) cells via the regulation of SMAD signaling and SOX2 expression[J]. Biochem Biophys Res Commun, 2019, 516(4): 1110-1115. DOI: 10.1016/j.bbrc.2019.07.011.
[28]	LIU YN, ABOU-KHEIR W, YIN JJ, et al. Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition[J]. Mol Cell Biol, 2012, 32(5): 941-953. DOI: 10.1128/MCB.06306-11.
[29]	LIU S, YANG H, CHEN Y, et al. Krüppel-like factor 4 enhances sensitivity of cisplatin to lung cancer cells and inhibits regulating epithelial-to-mesenchymal transition[J]. Oncol Res, 2016, 24(2): 81-87. DOI: 10.3727/096504016X14597766487717.
[30]	ZHANG P, HONG H, SUN X, et al. MicroRNA-10b regulates epithelial-mesenchymal transition by modulating KLF4/Notch1/E-cadherin in cisplatin-resistant nasopharyngeal carcinoma cells[J]. Am J Cancer Res, 2016, 6(2): 141-156.
[31]	LI Q, SONG W, WANG W, et al. Suppression of epithelial-mesenchymal transition in hepatocellular carcinoma cells by Krüppel-like factor 4[J]. Oncotarget, 2016, 7(20): 29749-29760. DOI: 10.18632/oncotarget.8831.
[32]	HE H, WU Z, LI S, et al. TRAF7 enhances ubiquitin-degradation of KLF4 to promote hepatocellular carcinoma progression[J]. Cancer Lett, 2020, 469: 380-389. DOI: 10.1016/j.canlet.2019.11.012.
[33]	XUE Y, JIA X, LI C, et al. DDX17 promotes hepatocellular carcinoma progression via inhibiting Klf4 transcriptional activity[J]. Cell Death Dis, 2019, 10(11): 814. DOI: 10.1038/s41419-019-2044-9.
[34]	SUNG MT, HSU HT, LEE CC, et al. Krüppel-like factor 4 modulates the migration and invasion of hepatoma cells by suppressing TIMP-1 and TIMP-2[J]. Oncol Rep, 2015, 34(1): 439-446. DOI: 10.3892/or.2015.3964.
[35]	YANG X, ZHANG D, LIU S, et al. KLF4 suppresses the migration of hepatocellular carcinoma by transcriptionally upregulating monoglyceride lipase[J]. Am J Cancer Res, 2018, 8(6): 1019-1029.
[36]	RAJASEKARAN D, JARIWALA N, MENDOZA RG, et al. Staphylococcal Nuclease and Tudor Domain Containing 1 (SND1 Protein) promotes hepatocarcinogenesis by inhibiting Monoglyceride Lipase (MGLL)[J]. J Biol Chem, 2016, 291(20): 10736-10746. DOI: 10.1074/jbc.M116.715359.
[37]	CHEN J, ZHANG L, MA S, et al. The aberrant expressions of MACC1, ZEB1, and KLF4 in hepatocellular carcinoma and their clinical significance[J]. Int J Clin Exp Pathol, 2019, 12(9): 3653-3661.
[38]	RIVERSO M, MONTAGNANI V, STECCA B. KLF4 is regulated by RAS/RAF/MEK/ERK signaling through E2F1 and promotes melanoma cell growth[J]. Oncogene, 2017, 36(23): 3322-3333. DOI: 10.1038/onc.2016.481.
[39]	ELEMENTO O. KLF4: A new player in plasma cell development[J]. Cell Cycle, 2016, 15(20): 2691-2692. DOI: 10.1080/15384101.2016.1214048.
[40]	BROSH R, ASSIA-ALROY Y, MOLCHADSKY A, et al. p53 counteracts reprogramming by inhibiting mesenchymal-to-epithelial transition[J]. Cell Death Differ, 2013, 20(2): 312-320. DOI: 10.1038/cdd.2012.125.
[41]	XU L, SUN H, ZHANG M, et al. MicroRNA-145 protects follicular granulosa cells against oxidative stress-induced apoptosis by targeting Krüppel-like factor 4[J]. Mol Cell Endocrinol, 2017, 452: 138-147. DOI: 10.1016/j.mce.2017.05.030.
[42]	ZHANG L, LI X, CHAO Y, et al. KLF4, a miR-32-5p targeted gene, promotes cisplatin-induced apoptosis by upregulating BIK expression in prostate cancer[J]. Cell Commun Signal, 2018, 16(1): 53. DOI: 10.1186/s12964-018-0270-x.
[43]	ZHANG Y, LIU Z, LI JS. Identifying biomarkers of hepatocellular carcinoma based on gene co-expression network from high-throughput data[J]. Stud Health Technol Inform, 2017, 245: 667-671.