Abstract
The role of Ras-related associated with diabetes (RRAD) in gastric cancer (GC) or colorectal cancer (CRC) has not been investigated. We aimed to investigate the biological and clinical roles of RRAD in GC and CRC and to assess RRAD as a therapeutic target. A total of 31 cancer cell lines (17 GC cell lines, 14 CRC cell lines), 59 patient-derived cells (PDCs from 48 GC patients and 11 CRC patients), and 84 matched pairs of primary cancer tissue and non-tumor tissue were used to evaluate the role of RRAD in vitro and in vivo. RRAD expression was frequently increased in GC and CRC cell lines, and siRNA/shRNA-mediated RRAD inhibition induced significant decline of tumor cell proliferation both in vitro and in vivo. A synergistic effect of RRAD inhibition was generated by combined treatment with chemotherapy. Notably, RRAD expression was markedly increased in PDCs, and RRAD inhibition suppressed PDC proliferation. RRAD inhibition also resulted in reduced cell invasion, decreased expression of EMT markers, and decreased angiogenesis and levels of associated proteins including VEGF and ANGP2. Our study suggests that RRAD could be a novel therapeutic target for treatment of GC and CRC, especially in patients with peritoneal seeding.
Highlights
RRAD is expressed in some malignant tumors such as breast cancer, leukemia, lymphoma, and glioma[9,12,13,14]
Altered expression of RRAD is frequently observed in cancer tissues, and it was associated with poor prognosis in several cancers including breast cancer, lung cancer[19], nasopharyngeal cancer[20], and ovarian cancer[21]
Quantitative RT-PCR assay and western blot assay showed that RRAD was markedly overexpressed in malignant cells of ascites, and RRAD inhibition resulted in suppression of cancer cell proliferation and invasion in colorectal cancer (CRC) and Gastric cancer (GC) cell lines
Summary
RRAD is expressed in some malignant tumors such as breast cancer, leukemia, lymphoma, and glioma[9,12,13,14]. Overexpression of RRAD in breast cancer is associated with invasiveness and poor prognosis[13]. RRAD knockdown induced mitochondrial apoptosis in leukemia and lymphoma cell lines[12]. Our group showed that RRAD knockdown could suppress tumor growth in prostate, breast, and stomach cell lines[15]. There has been little investigation of RRAD in GC or CRC, and the role of RRAD in GC remains unclear. We aimed to evaluate the biological role of RRAD in GC and CRC and to assess its potential as a therapeutic target
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