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