Circulating miR‐203 derived from metastatic tissues promotes myopenia in colorectal cancer patients

Abstract

Background Sarcopenia frequently occurs in metastatic cancer patients. Emerging evidence has revealed that various secretory products from metastatic tumours can influence host organs and promote sarcopenia in patients with malignancies. Furthermore, the biological functions of microRNAs in cell‐to‐cell communication by incorporating into neighbouring or distal cells, which have been gradually elucidated in various diseases, including sarcopenia, have been elucidated. Methods We evaluated psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) using pre‐operative computed tomography imaging in 183 colorectal cancer (CRC) patients. miR‐203 expression levels in CRC tissues and pre‐operative serum were evaluated using quantitative polymerase chain reaction. Functional analysis of miR‐203 overexpression was investigated in human skeletal muscle cells (SkMCs), and cells were analysed for proliferation and apoptosis. Expressions of several putative miR‐203 target genes (CASP3, CASP10, BIRC5, BMI1, BIRC2, and BIRC3) in SKMCs were validated. Results A total of 183 patients (108 men and 75 women) were included. The median age of enrolled patients at diagnosis was 68.0 years (range 35–89 years). High IMAC status significantly correlated with female gender ( P = 0.004) and older age ( P = 0.0003); however, no other clinicopathological factors correlated with IMAC status in CRC patients. In contrast, decreased PMI significantly correlated with female gender ( P = 0.006) and all well‐established disease development factors, including advanced T stage ( P = 0.035), presence of venous invasion ( P = 0.034), lymphovascular invasion ( P = 0.012), lymph node ( P = 0.001), distant metastasis ( P = 0.002), and advanced Union for International Cancer Control tumour–node–metastasis stage classification ( P = 0.0004). Although both high IMAC status and low PMI status significantly correlated with poor overall survival (IMAC: P = 0.0002; PMI: P < 0.0001; log‐rank test) and disease‐free survival (IMAC: P = 0.0003; PMI: P = 0.0002; log‐rank test), multivariate Cox's regression analysis revealed that low PMI was an independent prognostic factor for both overall survival (hazard ratio: 4.69, 95% confidence interval (CI): 2.19–10, P = 0.0001) and disease‐free survival (hazard ratio: 2.33, 95% CI: 1.14–4.77, P = 0.021) in CRC patients. Serum miR‐203 expression negatively correlated with pre‐operative PMI level ( P = 0.0001, ρ = −0.25), and multivariate logistic regression ana...

Management of Cancer Cachexia: Attempting to Develop New Pharmacological Agents for New Effective Therapeutic Options

“…As CC mediators, miRNAs seem to exert their action by favoring cell apoptosis, protein degradation, or causing downregulation of anabolic processes. For instance, circulating miR-203a-3p secreted by metastatic human colorectal cancer contributed to exacerbation of myopenia in pre-operative cancer patients by targeting survivin (BIRC5), a negative regulator of caspase-dependent apoptosis (67). MiR-21-5p and−206, instead, played an important role in the onset of muscle atrophy in mice under distinct muscledebilitating conditions, including CC.…”

Luteolin exhibits anti-breast cancer property through up-regulating miR-203

“…Herein, we for the first time illustrated miR-203 as another anti-tumour executor of luteolin. miR-203 has been widely identified as an anti-tumour miRNA [17][18][19][20], but its exact function in breast cancer is confusing. Two of the previous studies reported miR-203 as an oncogene, as silence of its expression inhibited breast cancer cells colony formation, transformation, stemness and migration [21,37].…”

“…miR-203 is one of such oncogenic miRNA that locates at chromosome 14q32.33. The antitumour role of miR-203 has been found in various kinds of cancers, such as colorectal cancer [17], hepatocellular carcinoma [18], gastric cancer [19], prostate cancer [20] and so forth. However, miR-203 exerted contradictory roles in breast cancer.…”

Non-coding RNAs as Putative Biomarkers of Cancer-Associated Cachexia

“…More recently, Okugawa et al, demonstrated that circulating miR-21 levels increased in cachectic colorectal cancer patients (Okugawa et al, 2018). Recently they also reported that circulating miR-203 is able to predict myopenia in metastatic colorectal cancer patients (Okugawa et al, 2019).…”