MARCKSL1 interacted with F-actin to promote esophageal squamous cell carcinoma mobility by modulating the formation of invadopodia.
MARCKSL1 interacted with F-actin to promote esophageal squamous cell carcinoma mobility by modulating the formation of invadopodia.
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MARCKSL1 与 F-肌动蛋白相互作用，通过调节侵袭伪足的形成促进食管鳞状细胞癌的迁移
DOI：
10.1002/cam4.5079
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发表时间：
2023-03
期刊：
影响因子：
4
通讯作者：
Mao, Yousheng
中科院分区：
文献类型：
--
作者：
Zhao, Yue;Xie, Xiufeng;Tian, Lusong;Liu, Fang;Sun, Yulin;Lu, Haizhen;Zhao, Xiaohang;Mao, Yousheng
新的证据表明，肉豆蔻酰化富含丙氨酸的 C 激酶底物 1 (MARCKSL1) 参与食管鳞状细胞癌 (ESCC) 的进展。然而，其基础机制尚不清楚。在这里，我们研究了 MARCKSL1 在 ESCC 进展中的机制。采用CCK8、Transwell和伤口愈合实验来测试MARCKSL1对体外增殖、侵袭和迁移的影响。接下来，通过 RNA 测序进行转录组分析，揭示 MARCKSL1 在 ESCC 进展中的潜在机制，随后通过蛋白质印迹和 qPCR 分析进行验证。此外，还进行了免疫荧光和明胶降解测定，以揭示 MARCKSL1 介导侵袭伪足形成和细胞外基质 (ECM) 降解的能力。最后，基于TCGA数据库分析和组织微阵列免疫组化染色评估MARCKSL1与ESCC患者临床病理特征的相关性。 MARCKSL1 的敲低显着减弱了 ESCC 细胞的体外运动能力，而 MARCKSL1 的过表达则具有相反的效果。转录组分析表明 MARCKSL1 介导 ESCC 细胞的移动性和迁移。此外，MARCKSL1 的过度表达增加了 F-肌动蛋白和皮质蛋白在迁移细胞前沿的共定位和 ECM 降解。此外，在食管癌患者中，食管癌（n = 182）中MARCKSL1的mRNA水平显着高于邻近食管上皮（n = 286），并且大样本量的肿瘤组织（n = 811）中MARCKSL1的表达水平显着高于非癌食管组织（n = 442）。 MARCKSL1 的较高表达与淋巴结转移呈正相关，并且与 ESCC 患者较差的生存率相关。 MARCKSL1 通过与 F-肌动蛋白和皮质蛋白相互作用来调节侵袭伪足的形成和 ECM 变性，从而促进细胞迁移和侵袭。 MARCKSL1高表达与有淋巴结转移的ESCC患者预后不良呈正相关。 MARCKSL1的高表达与有淋巴结转移的食管鳞状细胞癌（ESCC）患者的不良预后呈正相关。 MARCKSL1通过与F-actin和cortactin相互作用来调节侵袭伪足的形成和ECM变性，从而促进ESCC细胞的迁移和侵袭。 MARCKSL1可能成为食管癌的新生物标志物和治疗靶点。
Emerging evidence indicates that myristoylated alanine‐rich C kinase substrate like 1 (MARCKSL1) is involved in the progression of esophageal squamous cell carcinoma (ESCC). However, the underpinning mechanism is unclear. Here, we investigated the mechanisms involving MARCKSL1 in ESCC progression. CCK8, Transwell and wound‐healing assays were employed to test the effect of MARCKSL1 on proliferation, invasion and migration in vitro. Next, transcriptome profiling was conducted through RNA sequencing to reveal the underlying mechanism of MARCKSL1 in ESCC progression, which was subsequently verified by western blot and qPCR analysis. Moreover, immunofluorescence and gelatin degradation assays were performed to reveal the ability of MARCKSL1 to mediate invadopodia formation and extracellular matrix (ECM) degradation. Finally, the correlation between MARCKSL1 and the clinicopathological features of ESCC patients was assessed based on TCGA database analysis and immunohistochemistry staining of tissue microarrays. Knockdown of MARCKSL1 markedly attenuated the cell motility capacity of ESCC cells in vitro, while MARCKSL1 overexpression had the opposite effect. Transcriptomic analysis showed that MARCKSL1 mediated the mobility and migration of ESCC cells. In addition, overexpression of MARCKSL1 increased the colocalization of F‐actin and cortactin at the frontier edge of migrating cells and ECM degradation. Furthermore, in ESCC patients, the mRNA level of MARCKSL1 in esophageal carcinomas (n = 182) was found to be notably higher than that in adjacent esophageal epithelia (n = 286) and the expression levels of MARCKSL1 in the tumor tissues (n = 811) were significantly increased compared to those in noncancerous esophageal tissues (n = 442) with a large sample size. Higher expression of MARCKSL1 was positively correlated with lymph node metastasis and associated with worse survival rates of patients with ESCC. MARCKSL1 promotes cell migration and invasion by interacting with F‐actin and cortactin to regulate invadopodia formation and ECM degeneration. High MARCKSL1 expression is positively correlated with poor prognosis in ESCC patients with lymph node metastasis. High MARCKSL1 expression is positively correlated with poor prognosis in esophageal squamous cell carcinoma (ESCC) patients with lymph node metastasis. MARCKSL1 promotes ESCC cells migration and invasion by interacting with F‐actin and cortactin to regulate invadopodia formation and ECM degeneration. MARCKSL1 may be a new biomarker and therapeutic target for esophageal cancer.
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