Role of Sciellin in gallbladder cancer proliferation and formation of neutrophil extracellular traps

Abstract

Apart from primary tumor development and metastasis, cancer-associated thrombosis is the second cause of cancer death in solid tumor malignancy. However, the mechanistic insight into the development of gallbladder cancer (GBC) and cancer-associated thrombosis remains unclear. This study aimed to investigate the mechanistic role of Sciellin (SCEL) in GBC cell proliferation and the development of venous thromboembolism. The expression level of SCEL was determined by immunohistochemical staining. Roles of SCEL in gallbladder cancer cell were determined by molecular and cell biology methods. SCEL was markedly upregulated in GBC and associated with advanced TNM stages and a poor prognosis. Furthermore, SCEL interacted with EGFR and stabilized EGFR expression that activates downstream PI3K and Akt pathway, leading to cell proliferation. In addition, SCEL induces tumor cell IL-8 production that stimulates the formation of neutrophil extracellular traps (NETs), accelerating thromboembolism. In xenografts, SCEL-expressing GBCs developed larger tumors and thrombosis compared with control cells. The present results indicate that SCEL promotes GBC cell proliferation and induces NET-associated thrombosis, thus serving as a potential therapeutic target.

Neutrophil Extracellular Traps: A New Player in Cancer Metastasis and Therapeutic Target

“…Normally induced by pro-inflammatory factors during infection, NETs can also be stimulated by cancer cells and cancer-associated fibroblasts (CAF) in the absence of infection [ 40 ] , which hijacks antimicrobial immune system for cancer cell proliferation and metastasis (Table 2 ). The crosstalk between tumor cells and neutrophils can be mediated by tumor-derived chemokines, including granulocyte colony-stimulating factor (G-CSF) [ 41 , 42 ], IL-8 [ 43 , 44 ] and CXC Chemokine Receptor (CXC) ligands [ 45 ], which have been implicated in protumour NETosis in multiple murine models. In addition to chemokines, tumoral Cathepsin C, a cysteine protease essential for catalytic activation of serine proteases, has been shown to induce neutrophil ROS production and IL-1β secretion, thus promoting neutrophil infiltration and NETs formation [ 46 ] .…”

The regulatory mechanism of neutrophil extracellular traps in cancer biological behavior

“…A study discovered that CTSC secreted by tumors promotes the formation of NETs in breast cancer cells. CTSC induces neutrophil ROS production and the formation of NETs by activating the neutrophil membrane-bound PR3-interleukin-1β (IL-1β)-p38 axis [ 83 ].…”

Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

“…A recent study done by Li et al examined the function of Sciellin (SCEL), a precursor to the cornified envelope, which is a protective barrier in the upper epidermis [ 129 ], in gallbladder cancer progression. Using a co-culture experiment, the authors found that SCEL induced expression of NETs and citrullinated-histone 3, which is a critical marker of NET formation [ 130 ]. Similar to gallbladder cancer, SCEL is markedly elevated in pancreatic cancer [ 131 ].…”