ALKBH5对食管鳞状细胞癌恶性生物学行为的影响及相关机制研究

doi:10.3760/cma.j.cn371439-20240607-00012

国际肿瘤学杂志 ›› 2025, Vol. 52 ›› Issue (2): 79-88.doi: 10.3760/cma.j.cn371439-20240607-00012

ALKBH5对食管鳞状细胞癌恶性生物学行为的影响及相关机制研究

马培晗¹, 张灵敏², 李茜³, 路宁³, 温华³, 张明鑫³()

¹西安医学院第一附属医院麻醉科，西安 710077
²西安交通大学第一附属医院麻醉科，西安 710061
³西安医学院第一附属医院消化内科，西安 710077

收稿日期:2024-06-07 修回日期:2024-10-06 出版日期:2025-02-08 发布日期:2025-03-17
通讯作者: 张明鑫 E-mail:zmx3115@163.com
基金资助:
陕西省重点研发计划(2022JM-502);浙江省消化系肿瘤微创诊治与快速康复研究重点实验室开放课题资助项目(21SZDSYS16);西安医学院第一附属医院配套基金(XYFYPT-2023-04);西安医学院创新团队(2021TD15)

Effects of ALKBH5 on the malignant biological behavior of esophageal squamous cell carcinoma and the related mechanism

Ma Peihan¹, Zhang Lingmin², Li Qian³, Lu Ning³, Wen Hua³, Zhang Mingxin³()

¹Department of Anesthesiology， First Affiliated Hospital of Xi'an Medical University， Xi'an 710077， China
²Department of Anesthesiology， First Affiliated Hospital of Xi'an Jiaotong University， Xi'an 710061， China
³Department of Gastroenterology， First Affiliated Hospital of Xi'an Medical University， Xi'an 710077， China

Received:2024-06-07 Revised:2024-10-06 Online:2025-02-08 Published:2025-03-17
Contact: Zhang Mingxin E-mail:zmx3115@163.com
Supported by:
Key Research and Development Program of Shaanxi Province(2022JM-502);The Key Research Open Project of Minimally Invasive Diagnosis， Treatment and Rapid Rehabilitation of Digestive Tumors of Zhejiang Province(21SZDSYS16);Supporting Fund of the First Affiliated Hospital of Xi'an Medical University(XYFYPT-2023-04);Xi'an Medical University Innovation Team(2021TD15)

摘要/Abstract

摘要：

目的研究m⁶A去甲基化酶ALKBH5在食管鳞状细胞癌（ESCC）细胞中的作用及潜在机制。方法通过实时荧光定量PCR及蛋白质印迹法检测ALKBH5在正常食管黏膜上皮细胞（Het-1A）和ESCC细胞株（Eca109、KYSE30、KYSE150、KYSE410）中的表达；构建ALKBH5过表达/沉默的瞬转细胞株（siRNA转染后分为si-ALKBH5-1组、si-ALKBH5-2组）及对照细胞株；分别采用MTT法、细胞划痕实验、细胞凋亡实验研究ALKBH5对ESCC细胞增殖、迁移和凋亡的影响；通过转录组测序（RNA-seq）及甲基化RNA免疫共沉淀测序（MeRIP-seq）技术测序交集筛选出差异表达基因并采用RT-qPCR检测ALKBH5对该基因表达的影响。结果实时荧光定量PCR结果显示，ALKBH5 RNA在Het-1A、Eca109、KYSE30、KYSE150及KYSE410细胞株中的相对表达量分别为1.03±0.28、0.46±0.02、0.23±0.10、0.04±0.02、0.05±0.00，差异有统计学意义（F=444.60，P<0.001）；蛋白质印迹法显示，ALKBH5蛋白在Het-1A、Eca109、KYSE30、KYSE150及KYSE410细胞株中的相对表达量分别为1.14±0.03、0.88±0.04、0.66±0.01、0.69±0.01、0.95±0.01，差异有统计学意义（F=139.90，P<0.001）；MTT实验显示，KYSE30细胞对照组与ALKBH5过表达组72 h的吸光度（A）值分别为0.86±0.01、1.25±0.01，差异有统计学意义（t=46.93， P<0.001）；KYSE150细胞对照组与ALKBH5过表达组72 h的A值分别为1.00±0.03、1.43±0.02，差异有统计学意义（t=16.80， P<0.001）；KYSE30细胞对照组与si-ALKBH5-1、si-ALKBH5-2组96 h的A值分别为0.98±0.01、0.85±0.02、0.80±0.09，差异有统计学意义（F=72.97， P<0.001），KYSE30细胞对照组的A值均大于si-ALKBH5-1、si-ALKBH5-2组（均P<0.001）；KYSE410细胞对照组与si-ALKBH5-1、si-ALKBH5-2组72 h的A值分别为1.28±0.02、1.15±0.02、1.08±0.05，差异有统计学意义（F=16.97， P=0.003），KYSE410细胞对照组A值均大于si-ALKBH5-1、si-ALKBH5-2组（P=0.020；P=0.003）。细胞划痕实验显示，划痕后48 h，KYSE30细胞对照组与过表达ALKBH5组的迁移率分别为（27.39±0.54）%、（48.89±5.12）%，差异有统计学意义（t=5.90，P=0.004）；KYSE150细胞对照组与过表达ALKBH5组的迁移率分别为（39.67±0.43）%、（62.20±0.60）%，差异有统计学意义（t=43.15，P<0.001）；KYSE30细胞对照组与si-ALKBH5-1、si-ALKBH5-2组的迁移率分别为（25.08±1.86）%、（18.75±1.59）%、（7.67±0.52）%，差异有统计学意义（F=74.28，P<0.001），KYSE30细胞对照组的迁移率均大于si-ALKBH5-1、si-ALKBH5-2组（P=0.010；P<0.001）；KYSE410细胞对照组与si-ALKBH5-1、si-ALKBH5-2组的迁移率分别为（38.70±0.41）%、（28.27±1.01）%、（19.40±0.47）%，差异有统计学意义（F=400.20，P<0.001），KYSE410细胞对照组的迁移率均大于si-ALKBH5-1、si-ALKBH5-2组（均P<0.001）。细胞凋亡实验显示，KYSE30细胞对照组与过表达ALKBH5组的凋亡率分别为（9.59±0.88）%、（4.81±0.89）%，差异有统计学意义（t=6.23，P=0.001）；KYSE150细胞对照组与过表达ALKBH5组的凋亡率分别为（8.36±0.09）%、（6.42±0.19）%，差异有统计学意义（t=12.90，P<0.001）；KYSE30细胞对照组与si-ALKBH5-1、si-ALKBH5-2组的凋亡率分别为（4.31±0.19）%、（5.72±0.30）%、（8.94±0.71）%，差异有统计学意义（F=53.46，P<0.001），KYSE30细胞对照组的凋亡率均小于si-ALKBH5-1、si-ALKBH5-2组（P=0.049；P<0.001）；KYSE410细胞对照组与si-ALKBH5-1、si-ALKBH5-2组的凋亡率分别为（4.45±0.36）%、（5.40±0.11）%、（6.64±0.15）%，差异有统计学意义（F=43.36，P<0.001），KYSE410细胞对照组的凋亡率均小于si-ALKBH5-1、si-ALKBH5-2组（P=0.016；P<0.001）。通过RNA-seq及MeRIP-seq技术测序交集筛选出差异表达基因IGF2BP3，RT-qPCR结果显示，KYSE30中IGF2BP3的相对表达量在对照组和过表达ALKBH5组分别为1.01±0.10、1.41±0.10，差异有统计学意义（t=4.06，P=0.015）；KYSE150中IGF2BP3的相对表达量在对照组和过表达ALKBH5组分别为1.00±0.10、1.94±0.24，差异有统计学意义（t=5.08，P=0.007）；KYSE410中IGF2BP3的相对表达量在对照组和si-ALKBH5-1、si-ALKBH5-2组分别为1.01±0.14、0.67±0.04、0.41±0.04，差异有统计学意义（F=24.36，P=0.001），KYSE410对照组中IGF2BP3的相对表达量均大于si-ALKBH5-1、si-ALKBH5-2组（P=0.017；P=0.001）。结论 ALKBH5在ESCC细胞株中低表达，但ALKBH5过表达时可促进ESCC细胞的增殖和迁移，并抑制细胞凋亡，可能与某种负反馈调节机制有关。IGF2BP3可能是ALKBH5作用的下游靶点。

关键词: ALKBH5, 食道鳞癌, IGF2BP3

Abstract:

Objective To investigate the role and potential mechanism of m⁶A demethylase ALKBH5 in esophageal squamous cell carcinoma （ESCC）. Methods Real time fluorogenic quantitative PCR and Western blotting were used to detect ALKBH5 expression in normal esophageal epithelial cells （Het-1A） and ESCC cell lines （Eca109， KYSE30， KYSE150， KYSE410）. Transient cell lines with overexpression/knockdown of ALKBH5 （siRNA transfection was divided into si-ALKBH5-1 group and si-ALKBH5-2 group） and control cell lines were constructed. The effects of ALKBH5 on ESCC cell proliferation， migration and apoptosis were studied by MTT assay， cell scratch assay and cell apoptosis assay respectively. The differentially expressed gene was screened by the intersection of RNA sequencing （RNA-seq） and methylated RNA immunoprecipitation sequencing （MeRIP-seq） techniques， and the effect of ALKBH5 on the gene expression was detected by RT-qPCR. Results Real time fluorogenic quantitative PCR results showed that， the relative expression levels of ALKBH5 RNA in Het-1A， Eca109， KYSE30， KYSE150 and KYSE410 were 1.03±0.28， 0.46±0.02， 0.23±0.10， 0.04±0.02， 0.05±0.00， respectively， with a statistically significant difference （F=444.60， P<0.001）. Western blotting showed that， the relative expression levels of ALKBH5 protein in Het-1A， Eca109， KYSE30， KYSE150 and KYSE410 were 1.14±0.03， 0.88±0.04， 0.66±0.01， 0.69±0.01， 0.95±0.01， respectively， with a statistically significant difference （F=139.90， P<0.001）. MTT test showed that the absorbance （A） values of KYSE30 control group and ALKBH5 overexpression group were 0.86±0.01 and 1.25±0.01 after 72 hours， respectively， with a statistically significant difference （t=46.93， P<0.001）. The A values of KYSE150 control group and ALKBH5 overexpression group were 1.00±0.03 and 1.43±0.02 after 72 hours， respectively， with a statistically significant difference （t=16.80， P<0.001）. The A values of KYSE30 control group， si-ALKBH5-1 group and si-ALKBH5-2 group were 0.98±0.01， 0.85±0.02 and 0.80±0.09 after 96 hours， respectively， with a statistically significant difference （F=72.97， P<0.001）. The A values of KYSE30 control group were higher than those of si-ALKBH5-1 and si-ALKBH5-2 groups （both P<0.001）. The A values of KYSE410 control group， si-ALKBH5-1 group and si-ALKBH5-2 group were 1.28±0.02， 1.15±0.02 and 1.08±0.05 after 72 hours， respectively， with a statistically significant difference （F=16.97， P=0.003）. The A values in KYSE410 control group were higher than those in si-ALKBH5-1 group and si-ALKBH5-2 group （P=0.020； P=0.003）. The cell scratch test showed that 48 hours after scratch， the migration rates of KYSE30 cells in control group and ALKBH5 overexpression group were （27.39±0.54）% and （48.89±5.12）%， respectively， with a statistically significant difference （t=5.90， P=0.004）. The migration rates of KYSE150 cells in control group and ALKBH5 overexpression group were （39.67±0.43）% and （62.20±0.60）%， respectively， with a statistically significant difference （t=43.15， P<0.001）. The migration rates of KYSE30 cells in control group， si-ALKBH5-1 group and si-ALKBH5-2 group were （25.08±1.86）%，（18.75±1.59）% and （7.67±0.52）%， respectively， with a statistically significant difference （F=74.28， P<0.001）. The migration rates of KYSE30 cells in control group were higher than those of si-ALKBH5-1 group and si-ALKBH5-2 group （P=0.010； P<0.001）. The migration rates of KYSE410 cells in control group and si-ALKBH5-1 group， si-ALKBH5-2 group were （38.70±0.41）%，（28.27±1.01）% and （19.40±0.47）%， respectively， with a statistically significant difference （F=400.20， P<0.001）. The migration rates of KYSE410 cells in control group were higher than those of si-ALKBH5-1 group and si-ALKBH5-2 group （both P<0.001）. Apoptosis test showed that the apoptosis rates of KYSE30 cells in control group and ALKBH5 overexpression group were （9.59±0.88）% and （4.81±0.89）%， respectively， with a statistically significant difference （t=6.23， P=0.006）. The apoptosis rates of KYSE150 cells in control group and ALKBH5 overexpression group were （8.36±0.09）% and （6.42±0.19）%， respectively， with a statistically significant difference （t=12.90， P<0.001）. The apoptosis rates of KYSE30 cells in control group， si-ALKBH5-1 group and si-ALKBH5-2 group were （4.31±0.19）%，（5.72±0.30）% and （8.94±0.71）%， respectively， with a statistically significant difference （F=53.46， P<0.001）. The apoptosis rates in KYSE30 cells in control group were lower than those in si-ALKBH5-1 group and si-ALKBH5-2 group （P=0.049； P<0.001）. The apoptosis rates of KYSE410 control group， si-ALKBH5-1 group and si-ALKBH5-2 group were （4.45±0.36）%，（5.40±0.11）% and （6.64±0.15）%， respectively， with a statistically significant difference （F=43.36， P<0.001）. The apoptosis rates in KYSE410 cells in control group were lower than those in si-ALKBH5-1 group and si-ALKBH5-2 group （P=0.016； P<0.001）. The differentially expressed gene IGF2BP3 was screened by the intersection of RNA-seq and MeRIP-seq techniques， and the RT-qPCR results showed that， the relative expression levels of IGF2BP3 in KYSE30 were 1.01±0.10 and 1.41±0.10 in control group and ALKBH5 overexpression group， respectively， with a statistically significant difference （t=4.06， P=0.015）. The relative expression levels of IGF2BP3 in KYSE150 were 1.00±0.10 and 1.94±0.24 in control group and ALKBH5 overexpression group， respectively， with a statistically significant difference （t=5.08， P=0.007）. The relative expression levels of IGF2BP3 in KYSE410 were 1.01±0.14， 0.67±0.04 and 0.41±0.04 in control group， si-ALKBH5-1 group and si-ALKBH5-2 group， respectively， with a statistically significant difference （F=24.36， P=0.001）. The relative expression levels of IGF2BP3 in KYSE410 control group were higher than those in si-ALKBH5-1 group and si-ALKBH5-2 group （P=0.017； P=0.001）. Conclusions ALKBH5 is underexpressed in ESCC cell lines， but the overexpression of ALKBH5 can promote the proliferation and migration of ESCC cells and inhibit cell apoptosis， which may be related to some negative feedback regulation mechanism. IGF2BP3 may be the downstream target of ALKBH5.

Key words: ALKBH5, Esophageal squamous cell carcinoma, IGF2BP3

马培晗, 张灵敏, 李茜, 路宁, 温华, 张明鑫. ALKBH5对食管鳞状细胞癌恶性生物学行为的影响及相关机制研究[J]. 国际肿瘤学杂志, 2025, 52(2): 79-88.

Ma Peihan, Zhang Lingmin, Li Qian, Lu Ning, Wen Hua, Zhang Mingxin. Effects of ALKBH5 on the malignant biological behavior of esophageal squamous cell carcinoma and the related mechanism[J]. Journal of International Oncology, 2025, 52(2): 79-88.

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ALKBH5对食管鳞状细胞癌恶性生物学行为的影响及相关机制研究

Effects of ALKBH5 on the malignant biological behavior of esophageal squamous cell carcinoma and the related mechanism

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