m(6)A demethylase ALKBH5 suppression contributes to esophageal squamous cell carcinoma progression.
m(6)A demethylase ALKBH5 suppression contributes to esophageal squamous cell carcinoma progression.
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DOI：
10.18632/aging.203490
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发表时间：
2021-09-07
期刊：
影响因子：
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通讯作者：
Sun Y
中科院分区：
文献类型：
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作者：
Xiao D;Fang TX;Lei Y;Xiao SJ;Xia JW;Lin TY;Li YL;Zhai JX;Li XY;Huang SH;Jia JS;Tian YG;Lin XL;Cai KC;Sun Y
食管鳞状细胞癌（ESCC）是一种高度恶性的胃肠道肿瘤，复发率高，预后差。虽然N6-甲基腺苷（m6 A），最丰富的表观修饰的mRNA，已涉及在几种癌症，很少有人知道它参与ESCC的进展。我们发现ALKBH 5（一种m6 A脱甲基酶）在ESCC组织标本中的表达减少，在T3-T4、N1-N3、临床III-IV期和组织学III级肿瘤中的作用更明显，表明其参与晚期ESCC。ALKBH 5的外源性表达抑制ESCC细胞的体外增殖，而内源性ALKBH 5的耗竭显著增强ESCC细胞的体外增殖。这表明ALKBH 5对ESCC生长发挥抗增殖作用。此外，ALKBH 5过表达抑制裸鼠中Eca-109细胞的肿瘤生长;相反，内源性ALKBH 5的消耗加速体内TE-13细胞的肿瘤生长。ALKBH 5过表达的生长抑制作用部分归因于G1期阻滞。此外，ALKBH 5过表达减少了ESCC细胞的体外迁移和侵袭。总之，我们的研究结果表明，ALKBH 5表达的损失有助于ESCC恶性。
Esophageal squamous cell carcinoma (ESCC) is a highly malignant gastrointestinal cancer with a high recurrence rate and poor prognosis. Although N6-methyladenosine (m6A), the most abundant epitranscriptomic modification of mRNAs, has been implicated in several cancers, little is known about its participation in ESCC progression. We found reduced expression of ALKBH5, an m6A demethylase, in ESCC tissue specimens with a more pronounced effect in T3-T4, N1-N3, clinical stages III–IV, and histological grade III tumors, suggesting its involvement in advanced stages of ESCC. Exogenous expression of ALKBH5 inhibited the in vitro proliferation of ESCC cells, whereas depletion of endogenous ALKBH5 markedly enhanced ESCC cell proliferation in vitro. This suggests ALKBH5 exerts anti-proliferative effects on ESCC growth. Furthermore, ALKBH5 overexpression suppressed tumor growth of Eca-109 cells in nude mice; conversely, depletion of endogenous ALKBH5 accelerated tumor growth of TE-13 cells in vivo. The growth-inhibitory effects of ALKBH5 overexpression are partly attributed to a G1-phase arrest. In addition, ALKBH5 overexpression reduced the in vitro migration and invasion of ESCC cells. Altogether, our findings demonstrate that the loss of ALKBH5 expression contributes to ESCC malignancy.