Department of Pathology & Cancer Research Center, Yanbian University, Yanji, 133002, China.
Key Laboratory of the Science and Technology Department of Jilin Province, Yanji, 133002, China.
Cell Oncol (Dordr). 2022 Feb;45(1):69-84. doi: 10.1007/s13402-021-00652-7. Epub 2021 Dec 2.
Sparc/osteonectin, cwcv and kazal-like domain proteoglycan 1 (SPOCK1) has been reported to function as an oncogene in a variety of cancer types. Increasing evidence suggests that SPOCK1 contributes to the metastatic cascade, including invasion, epithelial-mesenchymal transition (EMT) and micro-metastasis formation. As yet, however, the underlying mechanism is not clearly understood. Here, we evaluated the expression and clinicopathological significance of SPOCK1 in primary pancreatic cancer (PC) specimens and explored the mechanisms underlying SPOCK1-mediated PC cell growth and metastasis.
The clinical relevance of SPOCK1 was evaluated in 81 patients with PC. The effect of SPOCK1 on proliferation, cell cycle progression, EMT and metastasis was examined in vitro and in vivo. The molecular mechanisms involved in SPOCK1-mediated regulation of NF-κB-dependent EMT were assessed in PC cell lines.
We found that SPOCK1 expression was increased in PC tissues and was associated with lymph node metastasis. Silencing or exogenous overexpression of SPOCK1 markedly altered the proliferation of PC cells through cell cycle transition. Overexpression of SPOCK1 promoted PC cell migration and invasion by regulating EMT progression. Moreover, we found that SPOCK1 contributes to EMT and metastasis by activating the NF-κB signalling pathway via direct interaction with IκBα. After NF-κB pathway inhibition by BAY11-7082, we found that PC cell motility and EMT induced by SPOCK1 were reversed.
From our data we conclude that SPOCK1 promotes PC metastasis via NF-κB-dependent EMT by interacting with IκBα. This newly identified mechanism may provide novel clues for the (targeted) treatment of PC patients.
Sparc/osteonectin、cwcv 和 kazal 样结构域蛋白聚糖 1（SPOCK1）已被报道在多种癌症类型中作为癌基因发挥作用。越来越多的证据表明，SPOCK1 有助于转移级联反应，包括侵袭、上皮-间充质转化（EMT）和微转移形成。然而，目前其潜在机制尚不清楚。在这里，我们评估了 SPOCK1 在原发性胰腺癌（PC）标本中的表达及其与临床病理的相关性，并探讨了 SPOCK1 介导的 PC 细胞生长和转移的机制。
在 81 例 PC 患者中评估了 SPOCK1 的临床相关性。在体外和体内研究了 SPOCK1 对增殖、细胞周期进程、EMT 和转移的影响。在 PC 细胞系中评估了 SPOCK1 介导的 NF-κB 依赖性 EMT 调节的分子机制。
我们发现 SPOCK1 在 PC 组织中的表达增加，并与淋巴结转移相关。SPOCK1 的沉默或过表达显著改变了 PC 细胞的增殖，通过细胞周期过渡。过表达 SPOCK1 通过调节 EMT 进展促进 PC 细胞迁移和侵袭。此外，我们发现 SPOCK1 通过与 IκBα 直接相互作用，激活 NF-κB 信号通路，促进 EMT 和转移。在用 BAY11-7082 抑制 NF-κB 通路后，我们发现 SPOCK1 诱导的 PC 细胞迁移和 EMT 被逆转。
从我们的数据中得出结论，SPOCK1 通过与 IκBα 相互作用，通过 NF-κB 依赖性 EMT 促进 PC 转移。这一新发现的机制可能为 PC 患者的（靶向）治疗提供新的线索。
