Abstract
BackgroundMalignant growth and metastasis of gastrointestinal stromal tumors (GIST) occur in some patients even during the course of treatment, but their mechanisms remains poorly understand at the molecular level so far.MethodsProfiles of protein expression in gastric GIST tissues were explored using protein microarray analysis, down-regulation of SPARCL1 (secreted protein acidic and rich in cysteine-like protein 1) was validated by RT-qPCR, western blot and immunohistochemistry. The effect of specific shRNA-induced SPARCL1 downregulation on the biological traits of GIST 882 cell was investigated. We then employed a mouse xenograft model to investigate whether the low-expression of SPARCL1 impact the metastasis ability of GIST cells in vivo.ResultsSPARCL1 was significantly downregulated in the gastric GIST with high-grade malignance as compared with low-grade malignance, its expression was closely correlated with tumor size, mitotic index, distant metastasis at the time of initial diagnosis and tumor progression of GIST (P < 0.05). Moreover, results of the Cox analysis showed that expression of SPARCL1 is an independent prognostic predictors for gastric GIST (P = 0.008; HR 0.157, 95% CI 0.040~ 0.612). Downregulation of SPARCL1 promoted cell migration and invasion, but did not affect proliferation, cell cycle and apoptosis of GIST 882 cells. In mouse xenograft model, GIST cells with the decreased expression of SPARCL1 presented an enhanced ability of liver metastasis (P < 0.05).ConclusionsTaken together, our present study demonstrated that SPARCL1 have a certain degree of malignancy-suppressing potential through inhibiting the metastasis of gastric GIST.
Highlights
Malignant growth and metastasis of gastrointestinal stromal tumors (GIST) occur in some patients even during the course of treatment, but their mechanisms remains poorly understand at the molecular level so far
SPARCL1 expression was decreased in tumors of High-grade malignancy (HGM) in accordance with microarray and Polymerase chain reaction (PCR) data (Fig. 2b, c). These data suggested that the downregulation of SPARCL1 in GIST might be responsible for the pathogenesis and progression, and we further investigated the functional role of SPARCL1 in gastric GIST
Except the highly collinear variables, into the Cox multivariate regression proportional hazards model, we found that radical degree (HR 7.266, 95% CI 1.222~ 43.221; P = 0.029), tumor size (HR 4.518, 95% CI 1.172~ 17.410; P = 0.028), and SPARCL1 expression (HR 0.157, 95% CI 0.040~ 0.612; P = 0.008) were independent prognostic predictors in gastric GIST (Table 5)
Summary
Malignant growth and metastasis of gastrointestinal stromal tumors (GIST) occur in some patients even during the course of treatment, but their mechanisms remains poorly understand at the molecular level so far. Gastrointestinal stromal tumors (GIST) is by far the most common mesenchymal neoplasm in the human digestive tract, which originating from the interstitial cells of Cajal or their progenitor cells [1, 2]. As reported in previous study, gastric GIST have become malignant progression from preexisting less aggressive tumors, namely a stepwise progression from low- to high-grade malignancy [10]. The molecular events involved in GIST malignization remains unclear by far. A better understanding of the molecular mechanism responsible for GIST metastasis is of critical significance, and would eventually result in new anticancer drug targets and greatly contribute to advances in diagnostic approaches
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