Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China.
Department of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
Histol Histopathol. 2024 Jun;39(6):747-760. doi: 10.14670/HH-18-678. Epub 2023 Nov 22.
Lysosomal-associated transmembrane protein 5 (LAPTM5) has been associated with poor prognosis in cancer patients. Its role in regulating metastasis in pancreatic ductal adenocarcinoma (PDAC), however, remains vague. The study here aimed to expound the metastasis-promoting properties of LAPTM5 in PDAC and the detailed mechanism. LAPTM5 was overexpressed in metastatic PDAC cells and was related to the dismal prognosis of patients in GEO datasets. By using lentiviral vectors harboring short hairpin RNA, we found that LAPTM5 downregulation reduced PDAC cell viability, proliferation, and aggressiveness and liver metastasis . Zinc finger with KRAB and SCAN domains 5 (ZKSCAN5) was predicted and verified to mediate LAPTM5 transcription in PDAC cells. Both ZKSCAN5 and SET domains, containing lysine methyltransferase 7 (SETD7) bound to the LAPTM5 promoter, and ZKSCAN5 recruited SETD7 to form a complex promoting LAPTM5 transcription. LAPTM5 knockdown reversed the promoting effect of ZKSCAN5 on the metastasis of PDAC cells. Thus, our findings on the ZKSCAN5/SETD7/LAPTM5 axis provide insights into the underlying mechanism of liver metastasis dissemination in PDAC.
溶酶体相关跨膜蛋白 5（LAPTM5）与癌症患者的预后不良有关。然而，其在调节胰腺导管腺癌（PDAC）转移中的作用尚不清楚。本研究旨在阐述 LAPTM5 在 PDAC 中的促转移作用及其详细机制。LAPTM5 在转移性 PDAC 细胞中过表达，并与 GEO 数据集患者的预后不良相关。通过使用携带短发夹 RNA 的慢病毒载体，我们发现 LAPTM5 下调降低了 PDAC 细胞的活力、增殖和侵袭性，并且减少了肝转移。锌指结构域含有 KRAB 和 SCAN 结构域 5（ZKSCAN5）被预测并验证为 PDAC 细胞中 LAPTM5 转录的介质。ZKSCAN5 和 SET 结构域都包含结合 LAPTM5 启动子的赖氨酸甲基转移酶 7（SETD7），并且 ZKSCAN5 将 SETD7 募集到形成复合物，从而促进 LAPTM5 转录。LAPTM5 敲低逆转了 ZKSCAN5 对 PDAC 细胞转移的促进作用。因此，我们关于 ZKSCAN5/SETD7/LAPTM5 轴的发现为 PDAC 中肝转移扩散的潜在机制提供了新的见解。
