SPARCL1 Modulates the Tumor Microenvironment and Suppresses Colorectal Cancer and Liver Metastasis through the CCL20/CCR6 Axis

Background and Purpose: To investigate the expression and biological functions of secreted protein acidic and rich in cysteine-like 1 (SPARCL1) in the tumor microenvironment of colorectal cancer liver metastases (CRCLM). More over the study aimed to provide a new molecular marker for targeted therapy.Methods: Thirty male C57BL6/J mice were randomly divided into the control group (n = 3), the CRCLM group (n = 7), the CRCLM+Lv-vector group (n = 5), the CRCLM+Lv-SPARCL1 group (n = 5), the CRCLM+Lv-vector shRNA group (n = 5), and the CRCLM+Lv-SPARCL1 shRNA group (n = 5). Mice liver tissues in each group was obtained. The histopathological changes and indexes were measured by hematoxylin and eosin (H&E) staining, Reverse transcription quantitative PCR (polymerase chain reaction) (RT-qPCR), western blot, Masson staining, Enzyme-linked immunosorbent assay (ELISA), and flow cytometry.Results: SPARCL1 mRNA and protein expression levels in the CRCLM group decreased compared to the control group (p < 0.05). Further SPARCL1 upregulation reduced the metastatic foci number, collagen area (%), expression of collagen I, collagen III, alpha-SMA (sarcomeric actin), CCL20 (chemokine CC-motif ligand 20), CCR6 (CC chemokine receptor 6), N-cadherin, and vi-mentin, percentage of Th17 cells, and IL (interleukin)-1 beta, IL-17, and TNF (tumor necrosis factor)-alpha content (p < 0.05). However, E-cadherin expression and IL-6, IL-8, and IL-10 content increased (p < 0.05). In contrast, downregulating SPARCL1 reversed the above index trends.Conclusions: SPARCL1 effectively reduced liver metastasis, collagen deposition, and liver fibrosis. Furthermore, it activated CCL20/CCR6 axis to inhibit immune responses and epithelial-to-mesenchymal transition (EMT), thus providing an experimen-tal basis for targeted therapy.

Automated summary

The study aimed to investigate the expression and biological functions of SPARCL1 in the tumor microenvironment of colorectal cancer liver metastases (CRCLM) and provide a new molecular marker for targeted therapy. The results showed that upregulation of SPARCL1 could reduce the metastatic foci number, collagen deposition, and liver fibrosis, and play an important role in immune responses and epithelial-to-mesenchymal transition (EMT).