Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Recent study found an increased level of glypican-1 positive (GPC1+) plasma exosomes in patients with stage II CRC, but decreased levels of plasma miR-96-5p and miR-149. This study further investigated the clinical significance of plasma GPC1+ exosomes and plasma miR-96-5p and miR-149 levels in stage III CRC patients. To study the effect of these microRNAs on GPC1+ plasma exosomes, we isolated and purified exosomes and overexpressed human GPC1 and the microRNAs miR-96-5p and miR-149 by adenovirus vectors. Overexpression of GPC1 activated epithelial-mesenchymal transition (EMT) which then increased invasion and migration in HT29 and HCT-116 colon cancer cells. In contrast, silencing GPC1 expression and overexpressing miR-96-5p and miR-149 significantly inactivated EMT and decreased invasion and migration of HT29 and HCT-116 cells. miR-96-5p and miR-149 inhibitors significantly increased invasion and migration of HT29 and HCT-116 cells. Our results indicate that high levels of circulating GPC1 positive exosomes before and after surgery as well as low circulating miR-96-5p and miR-149 before surgery indicated a severe clinical status and poor prognosis in stage III colon cancer patients. We conclude that GPC1 can be a biomarker for relapse of stage III CRC and may be involved in EMT activation, invasion, and migration of colorectal cancer cells.
Highlights
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers and the second leading cause of cancer-related deaths worldwide [1]
We observed higher levels of GPC1+ plasma exosomes in several other cases: in patients that died within two years versus patients that survived over two years (Figure 1B), in patients with relapse versus patients without relapse (Figure 1C), and in patients that died with relapse versus patients that survived with relapse (Figure 1D)
We found that a poor prognosis and relapse in stage III colon cancer patients could be predicted by the circulating GPC1+ exosomes, or the regulatory microRNA of GPC1
Summary
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers and the second leading cause of cancer-related deaths worldwide [1]. Surgery is the first option for resectable tumors while chemotherapy and radiotherapy are the main treatments for advanced diseases and are the adjuvant treatments for surgical therapy in CRC patients [2, 3]. Considerable progress has been made in screening, early diagnosis, and even individualized therapy, the morbidity of CRC is still high [4]. Www.impactjournals.com/oncotarget in stage II colorectal cancer patients, and 94%, 78%, 70%, and 66% in stage III patients at one, three, five, and seven years following surgery [5]. Recurrence is much higher for curative resection, as one study demonstrated a cumulative recurrence rate of 100% at 4 years in patients with curative resection [6].
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