Circulating miR-203 secreted from metastatic tissues could exacerbate myopenia in colorectal cancer patients.

Abstract

181 Background: Sarcopenia is commonly observed in advanced cancer patients with distant metastases. In addition, biological functions of microRNAs (miRNAs) in cell-to-cell communication by incorporating into neighboring or distal cells has been gradually elucidated in various diseases, including sarcopenia, have been established. Methods: First, we quantified miR-203 expression, a key miRNA involved in cell-to-cell communication, by qRT-PCR and in situ hybridization in 58 pairs of primary CRC (pCRC) and corresponding matched liver metastasis (LM) tissues. We further evaluated miR-203 levels using pCRC tissues and matched preoperative serum to clarify its clinical significance in independent 183 CRC patients. Second, we assessed psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) using preoperative computed tomography imaging to clarify its clinical burden and correlations with miR-203 levels in CRC patients. Functional analysis of miR-203 overexpression was investigated in human skeletal muscle cells (SkMC), and cells were analyzed for proliferation and apoptosis. Expression of several, putative, miR-203-target genes was also validated in SkMC cells. Results: MiR-203 expression was significantly upregulated in LM compared with matched pCRC tissues. Serum miR-203 levels were significantly upregulated in a stage-dependent manner, and high miR-203 expression was associated with poor survival in patients with CRC in both patient cohorts. In contrast to IMAC, decreased PMI significantly correlated with well-established disease development factors, and decreased PMI was an independent prognostic factor for both overall survival, and disease-free survival in CRC patients. Although tissue miR-203 expression did not significantly correlate with the body composition status, serum miR-203 expression negatively correlated with preoperative PMI level. Overexpression of miR-203 inhibited cell proliferation and induced apoptosis via downregulation of BIRC5 (Survivin) expression in SkMC cell. Conclusions: Assessment of serum miR-203 could be used for risk assessment of metastasis-related myopenia in CRC.