Background

N6-methyladenosine (m6A) modification has been identified to participate in cancer progression. However, the function of m6A modification in keloid, a kind of fibrous benign tumor, is still not fully explored. This study aimed to explore the function and mechanism of a m6A methyltransferase Wilm's tumor 1–associating protein (WTAP) in keloids formation.

Methods

The levels of WTAP and Homeobox A5 (HOXA5) in keloids were confirmed by qRT-PCR or western blotting analysis. The change of human keloid fibroblasts (HKFs) cell function was verified by CCK8, wound healing, and transwell assays. Besides, the m6A modification of HOXA5 caused by WTAP was determined by MeRIP assay.

Results

WTAP was upregulated in keloids, whereas HOXA5 was downregulated in keloids. Upregulating WTAP enhanced the abilities of HKFs proliferation, migration, and invasion, but upregulating HOXA5 showed the opposite effect on HKFs. Moreover, HOXA5 could be mediated the m6A modification by WTAP, and HOXA5 overexpression reversed the promotive effect of WTAP overexpression on HKFs by activating p53 pathway.

Conclusion

WTAP can mediate the m6A modification of HOXA5 to regulate p53 pathway, thereby accelerating keloids formation. Our findings provide new insights into the mechanisms of keloid formation by m6A modification, which may promote the development of targeted therapies for keloids to reduce the recurrence rate.

中文翻译：

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WTAP 通过介导 HOXA5 的 m6A 修饰抑制 p53 通路加速瘢痕疙瘩形成

背景

N6-甲基腺苷 (m6A) 修饰已被确定参与癌症进展。然而，m6A修饰在瘢痕疙瘩（一种纤维良性肿瘤）中的功能尚未得到充分探索。本研究旨在探讨 m6A 甲基转移酶 Wilm 肿瘤相关蛋白 (WTAP) 在瘢痕疙瘩形成中的功能和机制。

方法

通过 qRT-PCR 或蛋白质印迹分析证实了瘢痕疙瘩中 WTAP 和同源框 A5 (HOXA5) 的水平。通过 CCK8、伤口愈合和 Transwell 实验验证了人瘢痕疙瘩成纤维细胞 (HKF) 细胞功能的变化。此外，通过MeRIP分析测定了WTAP引起的HOXA5的m6A修饰。

结果

WTAP 在疤痕疙瘩中上调，而 HOXA5 在疤痕疙瘩中下调。上调WTAP可增强HKFs的增殖、迁移和侵袭能力，但上调HOXA5对HKFs表现出相反的作用。此外，HOXA5可以介导WTAP对m6A的修饰，HOXA5过表达通过激活p53通路逆转了WTAP过表达对HKFs的促进作用。

结论

WTAP可以介导HOXA5的m6A修饰来调节p53通路，从而加速疤痕疙瘩的形成。我们的研究结果为m6A修饰形成疤痕疙瘩的机制提供了新的见解，这可能会促进疤痕疙瘩靶向治疗的发展，以降低复发率。