Abstract
Malignant transformation of gastrointestinal stromal tumors (GISTs) is correlated with poor prognosis; however, the underlying biological mechanism is not well understood. In the present study, low-risk (LR) GISTs, GISTs categorized as high-risk based on tumor size (HBS), and on mitotic rate (HBM) were collected for RNA sequencing. Candidate hub lncRNAs were selected by Oncomine analysis. Expression of a selected hub lncRNA, DNM3OS, and its correlation with patients’ prognosis were analyzed using FISH staining, followed with the determination of function and underlying mechanism. Our results revealed a series of key pathways and hub lncRNAs involved in the malignant transformation of GISTs. Oncomine analysis revealed a tight association between clinical signatures and DNM3OS and suggested that DNM3OS is a hub lncRNA that is involved in the Hippo signaling pathway. In addition, DNM3OS was upregulated in HBS, HBM, and HBS/M GIST and correlated with worse prognosis in patients with GISTs. In addition, DNM3OS promoted GIST cell proliferation and mitosis by regulating the expression of GLUT4 and CD36. Collectively, these results improve our understanding of the malignant transformation of GISTs and unveil a series of hub lncRNAs in GISTs.
Highlights
Gastrointestinal stromal tumors (GISTs), relatively rare mesenchymal disease, are the most common human sarcoma of the gastrointestinal tract, with an estimated annual incidence of 10–15 per million [1]
MATERIALS AND METHODS Patients and tumor samples To construct the RNA sequencing data for gastrointestinal stromal tumors (GISTs), matched pairs of frozen normal and tumor tissues were collected from 10 patients (3 paired lowrisk GISTs [LR, tumor size 2–5 cm and mitotic rate ≤5 mitoses/50 high-power fields (HPFs)], 3 paired high-risk GISTs based on tumor size [high-risk based on tumor size (HBS), tumor size >10 cm and mitotic rate ≤5 mitoses/50 HPFs], and 4 paired high-risk GISTs based on mitotic rate [HBM, tumor size 2–5 cm and mitotic rate >10 mitoses/50 HPFs])
The results indicated that knockdown of DNM3OS in GIST cells inhibited the expression of GLUT4 and CD36 (Fig. 7C), suggesting that they function as oncogenes in GISTs
Summary
Gastrointestinal stromal tumors (GISTs), relatively rare mesenchymal disease, are the most common human sarcoma of the gastrointestinal tract, with an estimated annual incidence of 10–15 per million [1]. The metastasis rate for gastric GISTs ≤2 cm and a mitotic rate ≤5 mitoses/50 high-power fields (HPFs) and those >10 cm and a mitotic rate >5 mitoses/50 HPFs were 0% and 86%, respectively, according to the NCCN guidelines (Version 4; 2019). For gastric GISTs >10 cm, the metastasis rate for tumors with a mitotic rate ≤5 mitoses/50 HPFs and those with a mitotic rate >5 mitoses/50 HPFs were 12% and 86%, respectively (NCCN guidelines, Version 4; 2019). This evidence demonstrates the importance of tumor size and the mitotic index in evaluating the malignant transformation of GISTs. the biological mechanism underlying the malignant transformation of GISTs still remains unclear
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