Metastasis is still a major cause of cancer-related mortality. Lysosome-associated membrane protein 3 (LAMP3) has been implicated in the invasiveness and metastasis of multiple cancer types; however, the underlying mechanisms are unclear. In this study, we found that LAMP3 was overexpressed in esophageal squamous cell carcinoma (ESCC) tissues and that this increased expression positively correlated with lymph node metastasis. Depletion of LAMP3 dramatically suppressed the motility of ESCC cells in vitro and experimental pulmonary and lymph node metastasis in vivo. Importantly, knockdown of LAMP3 increased the level of phosphorylated VASP(Ser239), which attenuated the invasive and metastatic capability of ESCC cells. We identified that cAMP-dependent protein kinase A (PKA) was responsible for the phosphorylation of VASP at Ser239. Consistently, silencing of PKA regulatory subunits diminished Ser239 phosphorylation on VASP and restored the motility capacity of LAMP3-depleted ESCC cells. In conclusion, we uncovered a previously unknown role of LAMP3 in promoting cellular motility and metastasis in ESCC.

转移仍然是癌症相关死亡的主要原因。溶酶体相关膜蛋白 3 (LAMP3) 与多种癌症类型的侵袭和转移有关；然而，其根本机制尚不清楚。在这项研究中，我们发现LAMP3在食管鳞状细胞癌（ESCC）组织中过度表达，并且这种表达增加与淋巴结转移呈正相关。 LAMP3 的缺失显着抑制了体外ESCC 细胞的运动性以及体内实验性肺和淋巴结转移。重要的是，敲低LAMP3会增加磷酸化VASP（Ser239）的水平，从而减弱ESCC细胞的侵袭和转移能力。我们发现 cAMP 依赖性蛋白激酶 A (PKA) 负责 VASP Ser239 的磷酸化。一致地，PKA 调节亚基的沉默减少了 VASP 上 Ser239 的磷酸化，并恢复了 LAMP3 耗尽的 ESCC 细胞的运动能力。总之，我们发现了 LAMP3 在促进 ESCC 细胞运动和转移中的先前未知的作用。