现代预防医学

区域名称	引物序列	m⁶A修饰预测位点
SHIP2-1	F: 5’AAGGAGAAGGACCGGACTCA3’	1421TGTGTTTGAGAAGGAGAAGGACCGGACTCAGCGCAAGGACTTCATCTTTGTCAGTGCCCG1470
	R: 5’TCCTGCTTGGAGTGCTTGTT3’
SHIP2-2	F: 5’GGACCCAGGAGAACTCAGTG3’	1681TCTATGTCTTTGGGACCCAGGAGAACTCAGTGGGCGACCGCGAGTGGCTGGACCTACTGC1740
	R: 5’TTCCACAGTGATTGCATGGC3’
SHIP2-3	F: 5’CCAGACTTTCCACCTCCACC3’	3421GCACACTGCCCCCTCCAGACTTTCCACCTCCACCACTGCCGGACTCAGCCATCTTCCTGC3480

区域名称	引物序列	m⁶A修饰预测位点
SHIP2-1	F: 5’AAGGAGAAGGACCGGACTCA3’	1421TGTGTTTGAGAAGGAGAAGGACCGGACTCAGCGCAAGGACTTCATCTTTGTCAGTGCCCG1470
	R: 5’TCCTGCTTGGAGTGCTTGTT3’
SHIP2-2	F: 5’GGACCCAGGAGAACTCAGTG3’	1681TCTATGTCTTTGGGACCCAGGAGAACTCAGTGGGCGACCGCGAGTGGCTGGACCTACTGC1740
	R: 5’TTCCACAGTGATTGCATGGC3’
SHIP2-3	F: 5’CCAGACTTTCCACCTCCACC3’	3421GCACACTGCCCCCTCCAGACTTTCCACCTCCACCACTGCCGGACTCAGCCATCTTCCTGC3480

N6-甲基腺苷修饰通过抑制磷酸酶SHIP2表达促进砷诱导的皮肤细胞恶性表型

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蔡静思琳 , 方天禺 , 易广名 , 吴松轩 , 王志妍 , 张遵真 , 赵田禾

现代预防医学 | 环境与职业卫生 2026,53(12): 2153-2162

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现代预防医学 |环境与职业卫生 2026 , 53 (12) : 2153 -2162

N6-甲基腺苷修饰通过抑制磷酸酶SHIP2表达促进砷诱导的皮肤细胞恶性表型

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蔡静思琳, 方天禺, 易广名, 吴松轩, 王志妍, 张遵真, 赵田禾

作者信息

四川大学华西公共卫生学院/华西第四医院劳动卫生与环境卫生学系，四川成都 610041

通讯作者:

赵田禾，E-mail: zhaotianhe8@163.com

作者简介:

蔡静思琳（2000—），女，硕士在读，研究方向：环境卫生

N6-methyladenosine modification promotes arsenic-induced malignant phenotype of skin cells by inhibiting phosphatase SHIP2 expression

Jing-silin CAI, Tian-yu FANG, Guang-ming YI, Song-xuan WU, Zhi-yan WANG, Zun-zhen ZHANG, Tian-he ZHAO

Affiliations

Department of Occupational Health and Environmental Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan 610041, China

出版时间: 2026-06-25 doi: 10.20043/j.cnki.MPM.202601388

文章导航

摘要

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目的

探究m⁶A修饰是否通过抑制SHIP2蛋白表达促进砷诱导的皮肤细胞恶性表型。

方法

使用1 μmol/L亚砷酸钠连续染毒人皮肤角质形成细胞22周，取染毒0、4、8和22周的细胞作为长期砷暴露的细胞模型；使用3-脱氮腺苷（DAA）抑制细胞m⁶A修饰水平，ELISA试剂盒检测SHIP2蛋白表达量，m⁶A-IP-qPCR检测SHIP2 mRNA上的m⁶A修饰水平，RIP-qPCR检测m⁶A阅读蛋白与SHIP2 mRNA的结合水平，CCK-8实验、划痕愈合实验和软琼脂克隆形成实验用于检测细胞的恶性表型。

结果

砷染毒22周后，细胞SHIP2蛋白表达量显著降低（P<0.001），SHIP2 mRNA上三个特定区域的m⁶A修饰水平均升高（SHIP2-1：P=0.019；SHIP2-2：P=0.024；SHIP2-3：P=0.007），m⁶A阅读蛋白YTHDF2在SHIP2 mRNA的三个m⁶A修饰区域显著富集（SHIP2-1：P=0.004；SHIP2-2：P=0.015；SHIP2-3：P<0.05）。染毒22周细胞经DAA处理后SHIP2蛋白表达上调（P<0.001），SHIP2 mRNA上的m⁶A修饰水平显著降低（SHIP2-1：P=0.030；SHIP2-2：P=0.034；SHIP2-3：P=0.002），YTHDF2与SHIP2 mRNA的结合明显减弱（SHIP2-1：P=0.002；SHIP2-2：P=0.004；SHIP2-3：P<0.001）。砷染毒22周后细胞的迁移率和软琼脂克隆形成率增加（迁移率：P<0.001；软琼脂克隆形成率：P<0.001），DAA处理后细胞的迁移、增殖及软琼脂克隆形成能力均下降（迁移率：P<0.001；增殖率：P<0.001；软琼脂克隆形成率：P<0.001）。

结论

长期砷暴露通过时间依赖性上调细胞总m⁶A修饰水平和SHIP2 mRNA上的m⁶A修饰水平，增强m⁶A阅读蛋白YTHDF2与SHIP2 mRNA的结合，进而抑制SHIP2表达，最终促进人皮肤角质形成细胞的恶性表型。

关键词

N6-甲基腺苷修饰 / 磷脂酰肌醇5-磷酸酶SHIP2 / 亚砷酸钠 / 恶性表型

Abstract

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Objective

To investigate whether m⁶A modification promotes arsenic-induced malignant phenotype of skin cells by inhibiting SHIP2 protein expression.

Methods

Human skin keratinocytes were continuously exposed to 1 μmol/L sodium arsenite for 22 weeks, and cells were harvested at 0, 4, 8, and 22 weeks of exposure to establish the long-term arsenic treatment cell models. 3-deazaadenosine (DAA) was used to inhibit the m⁶A modification in cells. The SHIP2 protein expression level was detected by ELISA kit, the m⁶A modification level of SHIP2 mRNA was detected by m⁶A-IP-qPCR, the binding levels of m⁶A reader to specific m⁶A regions of SHIP2 mRNA was detected by RIP-qPCR, and the malignant phenotype of cells was detected by CCK-8 assay, scratch healing assay and soft agar colony formation assay, respectively.

Results

Exposure to NaAsO₂ for 22 weeks led to a significant decrease in SHIP2 protein expression (P<0.001). This reduction of SHIP2 protein expression was accompanied by increased m⁶A modification levels on SHIP2 mRNA at three specific regions (SHIP2-1: P=0.019; SHIP2-2: P=0.024; SHIP2-3: P=0.007), and enhanced binding levels of m⁶A reader YTHDF2 to SHIP2 mRNA (SHIP2-1: P=0.004; SHIP2-2: P=0.015; SHIP2-3: P<0.05). Conversely, DAA treatment upregulated SHIP2 protein expression (P<0.001), significantly reduced the m⁶A modification levels on SHIP2 mRNA (SHIP2-1: P=0.030; SHIP2-2: P=0.034; SHIP2-3: P=0.002), and downregulated the binding levels of YTHDF2 to SHIP2 mRNA (SHIP2-1: P=0.002; SHIP2-2: P=0.004; SHIP2-3: P<0.001). HaCaT cells exposed to NaAsO₂ for 22 weeks showed increased efficiency of migration and soft agar colony formation (migration: P<0.001; colony formation: P<0.001), and the cell migration rate, proliferation rate and soft agar colony formation rate were all reduced after DAA treatment (migration: P<0.001; proliferation: P<0.001; colony formation: P<0.001).

Conclusion

Long-term arsenic exposure time-dependently upregulates the total m⁶A modification levels of cells and the specific m⁶A modification levels on SHIP2 mRNA, which enhances the binding of the m⁶A reader YTHDF2 to SHIP2 mRNA, thereby inhibiting SHIP2 protein expression and ultimately promoting the malignant phenotype of human keratinocytes.

Key words

N6-methyladenosine / Phosphatidylinositol 5-phosphatase SHIP2 / Arsenic / malignant phenotype

引用本文

蔡静思琳, 方天禺, 易广名, 吴松轩, 王志妍, 张遵真, 赵田禾. N6-甲基腺苷修饰通过抑制磷酸酶SHIP2表达促进砷诱导的皮肤细胞恶性表型. 现代预防医学, 2026 , 53 (12) : 2153 -2162 . DOI: 10.20043/j.cnki.MPM.202601388

Jing-silin CAI, Tian-yu FANG, Guang-ming YI, Song-xuan WU, Zhi-yan WANG, Zun-zhen ZHANG, Tian-he ZHAO. N6-methyladenosine modification promotes arsenic-induced malignant phenotype of skin cells by inhibiting phosphatase SHIP2 expression[J]. Modern Preventive Medicine, 2026 , 53 (12) : 2153 -2162 . DOI: 10.20043/j.cnki.MPM.202601388

正文

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砷是广泛分布于水、土壤和大气中的I类致癌物^［1］，其致癌作用的主要靶器官是皮肤，饮用水砷浓度升高与皮肤基底细胞癌和鳞状细胞癌的发病风险增加显著相关^［2］。N6-甲基腺苷（N6-methyladenosine，m⁶A）修饰指腺嘌呤第6位N原子上的甲基化改变，是真核生物RNA中最丰富且可逆的甲基化修饰，在RNA转录后调控基因表达^［3-4］，研究显示砷暴露诱导m⁶A修饰水平上调是砷致细胞恶性转化过程中的重要环节^［5-6］。m⁶A修饰编码的表观遗传信息依赖m⁶A阅读蛋白的解读^［7］，YTHDF结构域家族蛋白（YTH domain family protein）是首先被鉴定出的且研究较为深入的m⁶A阅读蛋白^［8］，能特异性识别并结合靶mRNA上的m⁶A修饰进而调控基因表达^［9］。课题组前期研究发现，砷处理诱导人皮肤角质形成细胞恶性转化过程中，YTHDF2通过与m⁶A修饰的抑癌基因PTEN的mRNA结合抑制PTEN蛋白表达，降低PTEN对细胞增殖和存活关键信号通路—磷脂酰肌醇3-激酶（Phosphatidylinositol 3-Kinase，PI3K）/蛋白激酶B（Protein Kinase B，AKT）信号通路的负调控作用，显著增强细胞的增殖能力^［10-11］。

含SH2结构域的肌醇磷酸酶2（SH2-Containing Inositol Phosphatase2，SHIP2）是一种磷脂酰肌醇5-磷酸酶，与磷脂酰肌醇-3-磷酸酶类的PTEN在结构和功能上都具有相似性^［12］。SHIP2和PTEN都含有中央磷酸酶结构域，可以通过去磷酸化PI3K的产物—磷脂酰肌醇-3,4,5-三磷酸（PIP3），减少AKT被PIP3招募到细胞膜上，由此下调PI3K/AKT信号通路活性^［13］。已有研究表明，m⁶A修饰水平升高导致的SHIP2蛋白表达下调激活了PI3K/AKT信号通路，继而促进癌症进展^［14］。然而，m⁶A修饰能否抑制SHIP2蛋白表达促进砷诱导的细胞恶性转化尚未见报道。因此，本研究使用亚砷酸钠连续染毒人皮肤角质形成细胞22周，通过观察砷暴露过程中m⁶A修饰水平变化对SHIP2蛋白表达和细胞恶性表型的影响，探究m⁶A修饰是否通过抑制SHIP2蛋白表达介导砷的毒作用，为砷致皮肤细胞恶性转化寻找潜在的生物标志物。

1　材料和方法

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1.1　研究方法

1.1.1　主要试剂和仪器

永生化人皮肤角质形成细胞系（HaCaT细胞系，南京凯基生物科技有限公司），亚砷酸钠（NaAsO₂，纯度：99.0%，美国Fluka Chemical公司），EpiQuik m⁶A RNA甲基化定量试剂盒（美国Epigentek公司），3-脱氮腺苷（3-Deazaadenosine，DAA，美国APExBIO公司），Human Phosphatidylinositol 3,4,5-Trisphosphate 5-Phosphatase 2 （SHIP2）ELISA Kit试剂盒（英国Abbexa公司），DMEM高糖培养基和胎牛血清（塞维尔生物技术有限公司），CCK-8试剂（北京兰杰柯科技有限公司）；Multiskan Go酶标仪（美国Thermo Fisher公司）。

1.2　细胞培养及恶性转化细胞模型建立

永生化人皮肤角质形成细胞（HaCaT细胞）是被广泛用于研究人类皮肤病变的体外模型。人群流行病学研究表明，0.67~2 μmol/L饮用水砷暴露与皮肤癌的发生发展密切相关^［15］；课题组前期研究显示，1 μmol/L亚砷酸钠染毒22周（约50代）可显著增强HaCaT细胞的恶性表型^{［5,11,16］}。因此，本研究使用1 μmol/L亚砷酸钠连续处理HaCaT细胞22周，并保留染毒0、4、8和22周的细胞（分别对应未转化、可能早期转化、早期转化和恶性转化阶段），建立长期砷暴露诱导恶性转化的HaCaT细胞系。对照组（无亚砷酸钠染毒）和亚砷酸钠染毒组细胞均培养于含10%胎牛血清的DEME培养基，培养箱设置为37 ℃、5% CO₂。

1.3　细胞m⁶A修饰水平检测

1.3.1　细胞总m⁶A修饰水平检测

采用EpiQuik m⁶A RNA甲基化定量试剂盒检测细胞总m⁶A修饰水平，操作步骤参照试剂盒说明书进行，细胞总m⁶A修饰水平计算公式：m⁶A%=［（OD_sample -OD_NC） / S］ / ［（OD_PC - OD_NC） / P］×100%。

1.3.2　m⁶A-IP-qPCR检测SHIP2 mRNA上特定区域的m⁶A修饰水平

SHIP2 mRNA上的m⁶A修饰位点通过基于序列的RNA腺苷甲基化位点预测（sequence-based RNA adenosine methylation site predictor，SRAMP）方法进行预测^［5］，根据预测结果（表1），在SHIP2 mRNA上选择三个分别包含多个高置信度m⁶A修饰位点的特异性区域，并将这3个区域命名为SHIP2-1、SHIP2-2和SHIP2-3，针对这三个区域设计特异性PCR引物，再进行m⁶A-IP-qPCR实验检测SHIP2 mRNA上的m⁶A修饰水平，m⁶A-IP-qPCR参考课题组之前的研究方法进行^［10］。SHIP2-1、SHIP2-2和SHIP2-3区域的特异性引物序列及包含的m⁶A修饰位点如表1所示。

1.3.3　细胞m⁶A修饰水平抑制方法

3-Deazaadenosine（3-脱氮腺苷，DAA）是广泛应用于研究m⁶A调控作用的全局性甲基化抑制剂。DAA抑制常数（Ki）为3.9 μmol/L，本研究使用该浓度下的DAA溶液处理细胞24 h，收获m⁶A水平抑制后的细胞用于后续实验。

1.4　ELISA检测SHIP2蛋白表达量

使用Human Phosphatidylinositol 3,4,5-Trisphosphate 5-Phosphatase 2 （SHIP2） ELISA Kit试剂盒（英国Abbexa公司）检测细胞SHIP2蛋白表达量，操作参照试剂盒说明书进行，采用Multiskan GO酶标仪在450 nm处测定吸光度（OD）值，根据标准曲线计算各样本中SHIP2蛋白的浓度。

1.5　RIP-qPCR检测m⁶A阅读蛋白与SHIP2 mRNA上m⁶A修饰位点的结合情况

将细胞裂解液置于含蛋白酶和RNase抑制剂的多聚核糖体裂解缓冲液中处理后，使用DNase（20 U）去除基因组DNA，并在多聚体裂解缓冲液中制备蛋白A/G磁珠。原始细胞裂解液首先均分为两组，分别用于独立检测YTHDF1与SHIP2 mRNA以及YTHDF2与SHIP2 mRNA的结合情况。随后将每组裂解液再均分为三个等量样本，命名为YTHDF-IP、IgG-IP和Input。两份YTHDF-IP裂解液分别与YTHDF1特异性抗体（ab220162，Abcam，英国）和YTHDF2特异性抗体（ab220163，Abcam，英国）孵育，而IgG-IP则与同源IgG抗体孵育。4 ℃孵育过夜后，加入蛋白A/G磁珠孵育1 h捕获RNA蛋白复合物。经多聚核糖体洗涤缓冲液和DTT多次洗涤后，使用DTT和蛋白酶K在55 ℃孵育1 h洗脱结合的RNA。提取的RNA经逆转录后通过qPCR分析。SHIP2 mRNA上三个特异性m⁶A修饰位点的引物序列见表1。数据以Input组为基准进行标准化，并采用2^-ΔΔCt法计算相对结合水平。

1.6　细胞恶性表型检测

1.6.1　细胞增殖实验

将细胞（2 × 10³个/孔）接种于96孔板中，分别在培养0（细胞贴壁后）、24、48和72 h后弃培养基，PBS冲洗。每孔加入100 μl含10%CCK-8溶液的完全培养基，37 ℃避光孵育1.5 h后使用酶标仪测量450 nm波长处吸光度，并以培养0 h组的吸光度为基准，计算细胞增殖率。

1.6.2　划痕愈合实验

用记号笔在6孔板背面每隔0.5 cm画一条横线，再画一条经过孔中心的竖线垂直于所有横线，用于定位划痕位置。将细胞（1×10⁵个/孔）接种于6孔板，当细胞达到单层汇合状态时，用无菌200 μl移液枪头沿孔背面的竖线制造单一划痕，并弃去孔内培养基，PBS冲洗后每孔加入2 ml无血清培养基。使用倒置显微镜对划痕拍照，并使用ImageJ软件计算划痕面积，记为A₀。培养36 h后，再对同一位置的划痕拍照并计算面积，面积记为A₃₆。划痕迁移率（%）=（A₀ - A₃₆）×100/A₀。

1.6.3　软琼脂克隆形成实验

软琼脂克隆形成实验用于检测细胞的锚定非依赖性生长能力。将0.6%的低熔点琼脂以每孔50 μl加入96孔板铺平并凝固作为底层琼脂，再将每孔接种100 μl含有1 000个细胞和0.35%琼脂的完全培养基，并在37 °C下培养14天。倒置显微镜下计数细胞克隆（直径>75 mm），软琼脂克隆形成率（%）=（克隆数量/ 1 000）× 100。

1.7　统计分析

所有实验重复3次，经Shapiro-Wilk检验符合正态分布的计量资料以（均数±标准差）表示，采用SPSS 26进行统计分析。两组独立样本采用t检验，三组及三组以上的数据比较使用单因素方差分析（one-way analysis of variance, ANOVA）；不同处理条件和培养周数下的多组数据比较采用双因素方差分析（Two-way ANOVA），检验结果以q值与调整后的P值表示，检验水准α=0.05。

2　结果

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2.1　砷暴露时间依赖性上调细胞总m⁶A修饰水平，并抑制SHIP2蛋白表达

如图1A所示，培养8周和22周时，亚砷酸钠处理组细胞的总m⁶A修饰水平显著高于对照组细胞（8周：q =4.462，P=0.006；22周：q =9.536，P<0.001）。图1B显示，染毒22周细胞的SHIP2蛋白表达量约下降至染毒0周的细胞的53.13%（q =13.570，P<0.001）；培养8和22周时，染毒组细胞的SHIP2蛋白量分别下降至相同培养周数对照组细胞的70.62%和52.46%（8周：q =8.450，P<0.001；22周：q =13.940，P<0.001）。该结果表明，长期砷暴露时间依赖性上调细胞总m⁶A修饰水平并抑制SHIP2蛋白表达。

2.2　DAA处理抑制细胞总m⁶A修饰水平并恢复SHIP2蛋白表达

如图2A所示，亚砷酸钠染毒0、4、8和22周的细胞经DAA处理24 h后，总m⁶A修饰水平均显著下降（0周：q=4.539，P=0.006；4周：q=4.812，P=0.004；8周：q=6.920，P<0.001；22周：q=4.291，P=0.008），表明DAA处理能有效降低细胞总m⁶A修饰水平；图2B显示，亚砷酸钠染毒8周和22周的细胞经DAA处理后SHIP2蛋白表达水平上升（8周：q=5.023，P=0.003；22周：q=6.942，P<0.001），表明降低细胞总m⁶A修饰水平能逆转SHIP2蛋白表达抑制。

2.3　砷暴露上调SHIP2 mRNA的m⁶A修饰水平，DAA处理后SHIP2 mRNA的m⁶A修饰水平下降

基于SRAMP的预测结果，我们在SHIP2 mRNA上选择了三个分别包含多个m⁶A修饰位点的区域，并将这三个区域分别命名为SHIP2-1、SHIP2-2和SHIP2-3。如3A所示，与对照组细胞相比，亚砷酸钠染毒22周的细胞中SHIP2 mRNA上三个区域的m⁶A修饰水平均显著升高（SHIP2-1：t=3.311，P=0.019；SHIP2-2：t=3.168，P=0.024；SHIP2-3：t=3.843，P=0.007）；经DAA处理后，这三个区域的m⁶A修饰水平均下降（SHIP2-1：t=3.048，P=0.030；SHIP2-2：t=2.988，P=0.034；SHIP2-3：t=4.612，P=0.002）。该实验结果表明长期砷暴露会上调SHIP2 mRNA上的特异性m⁶A修饰水平，而DAA处理能有效抑制砷诱导的SHIP2 mRNA上的m⁶A修饰水平上调。

2.4　砷染毒22周细胞中m⁶A阅读蛋白YTHDF2在SHIP2 mRNA上显著富集

为明确砷暴露下SHIP2蛋白表达下调是否与m⁶A阅读蛋白YTHDFs相关，本研究接下来检测了YTHDFs与SHIP2 mRNA上m⁶A修饰区域的结合水平。YTHDFs的主要成员包括YTHDF1、YTHDF2和YTHDF3，考虑到在大多数细胞中，YTHDF3的主要功能是协同YTHDF1和YTHDF2调控基因表达^［9］，因此RIP-qPCR实验仅检测了YTHDF1和YTHDF2分别与SHIP2 mRNA的结合情况。如图4所示：YTHDF2在SHIP2 mRNA上的三个m⁶A修饰区域均显著富集（SHIP2-1：t=5.816，P=0.004；SHIP2-2：t=4.132，P=0.015；SHIP2-3：t=4.551，P<0.05，图4B），而YTHDF1仅在SHIP2-1区域富集（SHIP2-1：t=4.028，P=0.005，图4A）。该结果表明在砷染毒22周的细胞中，YTHDF2与SHIP2 mRNA的结合水平高于YTHDF1，提示YTHDF2可能介导了SHIP2蛋白表达下调。

2.5　DAA处理下调YTHDF2与SHIP2 mRNA的结合水平

如图5所示，DAA处理抑制染毒22周细胞中SHIP2 mRNA上的m⁶A修饰水平后，YTHDF2与SHIP2-1、SHIP2-2和SHIP2-3的结合水平均显著下降（SHIP2-1：t=4.513，P=0.002；SHIP2-2：t=3.995，P=0.004；SHIP2-3：t=5.924，P<0.001），表明抑制SHIP2 mRNA上的m⁶A修饰水平能降低YTHDF2与SHIP2 mRNA的结合。

2.6　m⁶A修饰对细胞恶性表型的影响

2.6.1　m⁶A修饰上调细胞迁移能力

如图6B所示，染毒8周和22周后细胞的迁移能力显著增加（8周：q=6.478，P<0.001；22周：q=13.760，P<0.001）；连续染毒8、22周细胞的迁移率相较于相同培养周数的对照组细胞均上升（8周：q=6.190，P<0.001；22周：q=12.030，P<0.001）；连续染毒8周和22周的细胞经DAA处理后，迁移率分别下降至未经DAA处理细胞84.68%、76.17%（8周：q=4.093，P=0.021；22周：q=8.104，P<0.001），表明砷暴露增强细胞的迁移能力，DAA处理下调细胞m⁶A修饰水平可以抑制砷诱导的细胞迁移能力上升。

2.6.2　抑制m⁶A修饰下调细胞增殖能力

课题组前期研究发现，长期砷暴露诱导m⁶A修饰水平上调会增强细胞增殖能力^［5］，因此本实验使用DAA处理细胞，观察抑制m⁶A修饰对细胞增殖能力的影响。

如图7A-B所示，染毒0和4周的细胞经DAA处理后未表现出增殖能力的差异（P > 0.05）；图7C-D显示，染毒8和22周的细胞经DAA处理后增殖率显著下降（8周：t=4.964，P<0.001；22周：t=8.704，P<0.001），这些结果表明下调细胞m⁶A修饰水平可以抑制细胞增殖。

2.6.3　m⁶A修饰上调细胞锚定非依赖性生长能力

如图8B所示，相较于亚砷酸钠染毒0周的细胞，染毒8周和22周细胞的软琼脂克隆形成率显著上升（8周：q=6.428，P<0.001；22周：q =15.39，P<0.001），且染毒22周细胞的软琼脂克隆形成率明显高于染毒8周细胞（q =8.961，P<0.001）；与相同培养周数的对照组细胞相比，染毒8和22周细胞的软琼脂克隆形成率明显增加（8周：q=4.772，P=0.007；22周：q =13.54，P<0.001），DAA处理后细胞软琼脂克隆形成率降低（8周：q=3.701，P=0.039；22周：q =5.941，P<0.001）。这些结果表明，亚砷酸钠长期染毒上调了细胞的锚定非依赖性生长能力，DAA处理抑制细胞m⁶A修饰水平可以使锚定非依赖性生长能力下降。

3　讨论

收起

作为被广泛研究的肿瘤调节因子，SHIP2可调控增殖信号PI3K/AKT、胰岛素信号和丝裂原活化蛋白激酶信号MAPK/ERK等多条通路影响癌症进展^［17］。本研究发现，长期砷暴露通过上调m⁶A修饰水平抑制SHIP2蛋白表达，进而增强HaCaT细胞的恶性表型，提示SHIP2作为抑癌因子参与了m⁶A修饰介导的砷致细胞恶性转化。值得注意的是，有多篇研究报道，SHIP2在食管鳞状细胞癌（eSCC）^［18］、喉鳞状细胞癌（LSCC）^［19］、PTEN缺失的胶质母细胞瘤^［20-21］以及乳腺癌^［22］和结直肠癌等多种癌症中^［23］均表现出促癌效应，表明SHIP2能以细胞环境依赖的方式发挥对癌症的双重调控作用。

SHIP2对癌症的双向调控可能与其对AKT活性的调节具有亚型特异性相关^［24］。AKT的亚型主要有AKT1和AKT2，AKT1作为细胞存活和生长的关键调节因子，在人体各组织中广泛表达；AKT2是维持葡萄糖稳态和代谢的核心蛋白，在多种癌症中驱动肿瘤细胞的侵袭和转移^［25］。SHIP2是磷脂酰肌醇5-磷酸酶，通过去磷酸化PIP3的5-磷酸生成磷脂酰肌醇-3,4-二磷酸（PI（3,4）P2）^［26］，这个过程虽然降低了细胞膜上PIP3含量，减少AKT1被PIP3招募至细胞膜和后续激活，但生成的PI（3,4）P2对AKT2的亲和力与PIP3接近，可维持AKT2的膜招募与部分激活^［27］。换言之，PI（3,4）P2虽然不像PIP3那样提供全亚型、高强度的AKT锚定和招募能力，但可以借助AKT2，以强度下调的方式延续AKT信号。因此SHIP2高表达既可通过降解PIP3抑制AKT1发挥抑癌作用，也能通过促进PI（3,4）P2生成选择性招募AKT2，维持细胞促生存信号进而发挥促癌作用^［28］。本研究中，DAA处理挽救SHIP2蛋白表达抑制后，细胞恶性表型发生逆转，提示SHIP2可能通过减少AKT1被招募到细胞膜上进而发挥抑癌作用，接下来的研究中可以继续检测SHIP2蛋白表达变化对PI3K/AKT信号通路强度的影响，以明确SHIP2是否通过调控PI3K/AKT信号通路参与m⁶A修饰介导的砷致癌。

本研究结果显示，长期砷暴露诱导恶性转化过程中细胞总m⁶A修饰水平升高，抑制总m⁶A修饰水平可以逆转细胞恶性表型，与前人的研究结果一致^［10］。然而也有研究证实，m⁶A修饰水平降低同样可促进亚砷酸盐诱导的细胞恶性表型，这归因于m⁶A修饰发生在不同功能的靶基因上^［29-30］。m⁶A修饰对肿瘤进程的调控表现出显著的背景特异性，其最终生物学效应不仅取决于发生m⁶A修饰的信号通路，更源于阅读蛋白对特定靶基因上m⁶A修饰的差异化解读^［9］。m⁶A调控机制的复杂性使得细胞总m⁶A水平无法精确反映砷致癌的具体病理进程，因此总m⁶A修饰水平并不适合作为监测砷诱导皮肤癌的生物标志物。本研究将总m⁶A水平细化到特定的SHIP2 mRNA分子上来探究m⁶A修饰介导砷致癌的机制，观察到下调SHIP2 mRNA上的m⁶A修饰水平可以有效降低YTHDF2与SHIP2 mRNA的结合，并挽救SHIP2蛋白表达抑制，后续可以继续探索靶向擦除SHIP2 mRNA的m⁶A修饰能否有效逆转细胞的恶性表型，验证SHIP2 mRNA的特异性m⁶A修饰是否有潜力作为砷诱导皮肤病变的可靠生物标志物。

综上所述，本研究发现，长期砷暴露通过上调细胞总m⁶A修饰水平和SHIP2 mRNA上的m⁶A修饰水平驱动m⁶A阅读蛋白YTHDF2与SHIP2 mRNA结合，进而抑制SHIP2蛋白表达，最终增强HaCaT细胞的增殖、迁移和锚定非依赖性生长能力；抑制m⁶A修饰可以挽救SHIP2蛋白表达下调并逆转细胞恶性表型。研究结果表明SHIP2是m⁶A修饰介导砷致皮肤细胞恶性转化的重要靶点，提示SHIP2 mRNA上的特异性m⁶A修饰可能作为砷致皮肤癌的潜在生物标志物。

基金

收起

国家自然科学基金青年项目(82404396)
四川省自然科学基金青年基金(2024NSFSC1805)

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2026年第53卷第12期

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文章信息

doi: 10.20043/j.cnki.MPM.202601388

接收时间：2026-01-23
首发时间：2026-09-28
出版时间：2026-06-25

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收稿日期：2026-01-23

基金

国家自然科学基金青年项目(82404396)

四川省自然科学基金青年基金(2024NSFSC1805)

作者信息

四川大学华西公共卫生学院/华西第四医院劳动卫生与环境卫生学系，四川成都 610041

通讯作者:

赵田禾，E-mail: zhaotianhe8@163.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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