MLLT1超伸长复合亚基在肝细胞癌发生发展中的作用及其临床意义

于华婧; 魏路阳; 刘姗姗; 管成剑; 张忠涛

doi:10.16098/j.issn.0529-1356.2023.04.008

PDF(19475 KB)

解剖学报 ›› 2023, Vol. 54 ›› Issue (4) : 425-433. DOI: 10.16098/j.issn.0529-1356.2023.04.008

MLLT1超伸长复合亚基在肝细胞癌发生发展中的作用及其临床意义

于华婧魏路阳刘姗姗管成剑张忠涛*

作者信息 +

Role and clinical significance of MLLT1 super elongation complex subunit in the occurrence and development of hepatocellular carcinoma

YU Hua-jing WEI Lu-yang LIU Shan-shan GUAN Cheng-jian ZHANG Zhong-tao*

Author information +

文章历史 +

摘要

目的探讨MLLT1超伸长复合亚基（MLLT1）在肝细胞癌发生中的作用以及其对肝细胞癌免疫微环境的影响。方法利用多因素Cox回归分析以及GEPIA、UALCAN等肿瘤基因分析工具，探讨MLLT1基因在不同肿瘤中的表达情况和预后改变；利用Real-time PCR、免疫印迹、免疫组织化学方法探讨MLLT1在肝细胞癌肿瘤组织和正常组织间的表达差异；利用MTT实验、细胞周期实验检测敲低MLLT1对细胞增殖和细胞周期的影响；探讨MLLT1与肿瘤微环境中免疫细胞及免疫浸润的相关性，以及与免疫新抗原、免疫检查点、肿瘤突变负荷和微卫星不稳定性的相关性。结果 MLLT1基因在包括肝细胞癌在内的多种实体瘤中异常表达，敲低MLLT1会抑制肝癌细胞增殖能力并对细胞周期造成阻滞，且MLLT1的高表达与肝细胞癌的不良预后相关。MLLT1的高表达也会影响肝细胞癌中CD4+T细胞、中性粒细胞等免疫细胞的浸润。结论 MLLT1在肝细胞癌中高表达，MLLT1能够影响肝癌细胞增殖和破坏细胞周期，并通过影响免疫微环境的稳态在肝细胞癌发生发展中扮演重要角色。

Abstract

Objective To investigate the role of MLLT1 in hepatocellular carcinoma （HCC）and its impact on the tumor immune microenvironment. Methods Multivariate Cox regression analysis and tumor gene analysis tools such as GEPIA and UALCAN were used to explore the expression of the MLLT1 gene and its prognostic significance in different tumors. Real-time PCR, Western blotting, and immunohistochemistry were used to investigate the differential expression of MLLT1 between HCC tumor tissue and normal tissue. MTT assay and cell cycle analysis were performed to assess the effect of MLLT1 knockdown on cell proliferation and cell cycle. The correlation between MLLT1 and immune cells, as well as immune infiltrates in the tumor microenvironment, and their correlation with immune neoantigens, immune checkpoints, tumor mutation burden, and microsatellite instability were also explored. Results The MLLT1 gene was found to be aberrantly expressed in various solid tumors including HCC, and its high expression was associated with poor prognosis in HCC. Knockdown of MLLT1 inhibited HCC cell proliferation and blocked the cell cycle. High expression of MLLT1 was found to affect the content of multiple immune cells, including CD4+T cells and neutrophile granulocyte cells in the HCC microenvironment. Conclusion MLLT1 is highly expressed in HCC and knockdown of MLLT1 can inhibit HCC cell proliferation and block the cell cycle. MLLT1 has a certain degree of impact on the immune microenvironment of HCC. Therefore, MLLT1 may serve as a potential diagnostic biomarker and therapeutic target for HCC.

导出引用

于华婧魏路阳刘姗姗管成剑张忠涛. MLLT1超伸长复合亚基在肝细胞癌发生发展中的作用及其临床意义[J]. 解剖学报. 2023, 54(4): 425-433 https://doi.org/10.16098/j.issn.0529-1356.2023.04.008

YU Hua-jing WEI Lu-yang LIU Shan-shan GUAN Cheng-jian ZHANG Zhong-tao. Role and clinical significance of MLLT1 super elongation complex subunit in the occurrence and development of hepatocellular carcinoma[J]. Acta Anatomica Sinica. 2023, 54(4): 425-433 https://doi.org/10.16098/j.issn.0529-1356.2023.04.008

中图分类号： R735.7

参考文献

［1］Villanueva A. Hepatocellular carcinoma ［J］. N Engl J Med, 2019, 380(15): 1450-1462.

［2］Forner A, Reig M, Bruix J. Hepatocellular carcinoma ［J］. Lancet, 2018, 391(10127): 1301-1314.

［3］Gao Q, Zhu H, Dong L, et al. Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma ［J］. Cell, 2019, 179(2): 561-577 e522. ［4］Yang Z, Yan C, Ma J, et al. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma ［J］. Nat Metab, 2023, 5(1): 61-79.

［5］Bayo J, Fiore EJ, Dominguez LM, et al. A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets ［J］. J Hepatol, 2019, 71(1): 78-90.

［6］Hu H, Saha N, Yang Y, et al. The ENL YEATS epigenetic reader domain critically links MLL-ENL to leukemic stem cell frequency in t(11;19) Leukemia ［J］. Leukemia, 2023, 37(1): 190-201.

［7］Takacova S, Slany R, Bartkova J, et al. DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo ［J］. Cancer Cell, 2012, 21(4): 517-531.

［8］ Ui A, Nagaura Y, Yasui A. Transcriptional elongation factor ENL phosphorylated by ATM recruits polycomb and switches off transcription for DSB repair ［J］. Mol Cell, 2015, 58(3): 46-482.

［9］Mueller D, Bach C, Zeisig D, et al. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification ［J］. Blood, 2007, 110(13): 4445-4454.

［10］Erb MA, Scott TG, Li BE, et al. Transcription control by the ENL YEATS domain in acute leukaemia ［J］. Nature, 2017, 543(7644): 270-274.

［11］Wan L, Wen H, Li Y, et al. ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia ［J］. Nature, 2017, 543(7644): 265-269.

［12］Liu Y, Li Q, Alikarami F, et al. Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia ［J］. Cancer Discov, 2022, 12(11): 2684-2709.

［13］Li C, Tang Z, Zhang W, et al. GEPIA2021: integrating multiple deconvolution-based analysis into GEPIA ［J］. Nucleic Acids Res, 2021, 49(W1): W242-W246.

［14］Tang Z, Li C, Kang B, et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses ［J］. Nucleic Acids Res, 2017, 45(W1): W98-W102.

［15］Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses ［J］. Neoplasia, 2017, 19(8): 649-658.

［16］Guan ChJ, Yu HJ, Zhang XD, et al. Expression and clinical significance of phosphoglycerate kinase 1 in hepatocellular carcinoma based on bioinformatics methods ［J］. Acta Anatomica Sinica, 2022, 53(6): 744-753. (in Chinese)

管成剑, 于华婧, 张小东, 等. 基于癌症多组学数据库深度解析磷酸甘油激酶1在肝细胞癌中的表达及临床意义［J］. 解剖学报, 2022, 53(6): 744-753.

［17］Zhang D, Tang Z, Huang H, et al. Metabolic regulation of gene expression by histone lactylation ［J］. Nature, 2019, 574(7779): 575-580.

［18］Yu H, Bu C, Liu Y, et al. Global crotonylome reveals CDYL-regulated RPA1 crotonylation in homologous recombination-mediated DNA repair ［J］. Sci Adv, 2020, 6(11): eaay4697.

［19］Sabari BR, Zhang D, Allis CD, et al. Metabolic regulation of gene expression through histone acylations ［J］. Nat Rev Mol Cell Bio, 2017, 18(2): 90-101.

［20］Zhao D, Guan H, Zhao S, et al. YEATS2 is a selective histone crotonylation reader ［J］. Cell Research, 2016, 26(5): 629-632.

［21］Li Y, Sabari Benjamin R, Panchenko T, et al. Molecular coupling of histone crotonylation and active transcription by AF9 YEATS domain ［J］. Mol Cell, 2016, 62(2): 181-193.

［22］Asiaban JN, Milosevich N, Chen E, et al. Cell-based ligand discovery for the ENL YEATS domain ［J］. ACS Chem Biol, 2020, 15(4): 895-903.

［23］Kabra A, Bushweller J. The intrinsically disordered proteins MLLT3 (AF9) and MLLT1 (ENL) -multimodal transcriptional switches with roles in normal hematopoiesis, MLL fusion leukemia, and kidney cancer ［J］. J Mol Biol, 2022, 434(1): 167117.

［24］Gougelet A. Epigenetic modulation of immunity: towards new therapeutic avenues in hepatocellular carcinoma ［J］? Gut, 2019, 68(10): 1727-1728.

［25］Wang S, Wu Q, Chen T, et al. Blocking CD47 promotes antitumour immunity through CD103(+) dendritic cell-NK cell axis in murine hepatocellular carcinoma model ［J］. J Hepatol, 2022, 77(2): 467-478.

［26］Tatsumi T, Takehara T, Kanto T, et al. B7-1 (CD80)-gene transfer combined with interleukin-12 administration elicits protective and therapeutic immunity against mouse hepatocellular carcinoma ［J］. Hepatology, 1999, 30(2): 422-429.

［27］Hattori E, Okumoto K, Adachi T, et al. Possible contribution of circulating interleukin-10 (IL-10) to anti-tumor immunity and prognosis in patients with unresectable hepatocellular carcinoma ［J］. Hepatol Res, 2003, 27(4): 309-314.

基金

ZBTB16-MTA3/NuRD复合体抑制肝细胞癌肝癌侵袭与转移的分子机制研究;ACAT1的巴豆酰化修饰通过调控脂肪酸氧化影响非酒精性脂肪性肝病发生发展的分子机制研究;CPT2的巴豆酰化修饰通过调控脂肪酸β氧化驱动非酒精性脂肪性肝病发生的机制研究;USP37促进肝细胞肝癌侵袭与转移的分子机制研究;USP37-MTA2/NuRD复合体促进肝细胞肝癌侵袭与转移的分子机制研究;北京市医院管理中心青苗计划