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Identification of serpin peptidase inhibitor clade A member 1 as a novel serum biomarker for gastric cancer and promotion of liver metastasis
Background
Approximately 9. 9%～18. 7% of gastric cancer (GC) patients experience liver metastasis (LM) during the course of the disease and is highly associated with poor prognosis. The development of sensitive biomarkers for detecting and predicting liver metastasis is required for a better clinical outcome. Serpin peptidase inhibitor clade A member 1 (SERPINA1) has been studied in several types of cancer; However, their functional in gastric cancer remains unknown. The present study aimed to evaluate SERPINA1 as a novel serum prognostic biomarker for gastric cancer and associated with liver metastasis.
Methods
A retrospective cohort with 68 surgically resected gastric cancer patients and a prospective cohort with 45 gastric cancer patients with liver metastasis from The Sixth Affiliated Hospital of Sun Yat-sen University were constructed. Immunohistochemistry was performed to evaluate expression of SERPINA1 protein in tissue specimens. Enzyme-linked immunosorbent assays (ELISAs) were used to analyze the serum specimens. Detailed clinicopathological parameters as well as patients' survival were recorded. A nomogram including SERPINA1 expression was also constructed and validated to predict the prognosis of gastric cancer patients. SERPINA1 protein expression was also analyzed by western blot in human GC derived cell lines and a normal epithelial cell line. Functional experiments were performed by overexpression and downregulation of SERPINA1 in GC derived cell lines and a normal epithelial cell line.
Results
Serum SERPINA1 expression was obviously increased and associated with tumor stage in gastric cancer patients, and its high expression was significantly related to differentiated phenotype and vessel invasion, as well as liver metastasis. High SERPINA1 expression was significantly associated with hepatic recurrence after curative surgery, and cumulative incidences of hepatic recurrence were significantly greater in patients with high SERPINA1 expression compared with patients with low SERPINA1 expression. High SERPINA1 expression indicated a poor prognosis, and monogram including serum SERPINA1 expression could predict the prognosis of gastric cancer patients effectively. Moreover, serum ITGB6 expression was associated with ITGB6 expression in tumor tissues. On the other hand, SERPINA1 showed differential expression GC cell lines. By using western blotting, wound-healing and invasion assays in cell lines, overexpression of SERPINA1 increased the migration and invasion of gastric cancer cells, whereas knockdown of SERPINA1 decreased these functions. Moreover, SERPINA1 overexpression increased the protein levels of VEGFR2, which is a key regulator of the VEGF signaling pathway.
Conclusions
The present study identified that SERPINA1 could serve as a novel serum biomarker for the risk stratification, prognostic prediction of gastric cancer patients and is also related to liver metastasis.
Legal entity responsible for the study
The authors.
Funding
The National Natural Science Foundation of China (Grant Nos 81902949).
Disclosures
All authors have declared no conflicts of interest.
