Exosome‐delivered miR‐221/222 exacerbates tumor liver metastasis by targeting SPINT1 in colorectal cancer

Abstract

MicroRNAs (miRNAs) are involved in the progression of many cancers through largely unelucidated mechanisms. The results of our present study identified a gene cluster, miR‐221/222, that is constitutively upregulated in serum exosome samples of patients with colorectal carcinoma (CRC) with liver metastasis (LM); this upregulation predicts a poor overall survival rate. Using an in vitro cell coculture model, we demonstrated that CRC exosomes harboring miR‐221/222 activate liver hepatocyte growth factor (HGF) by suppressing SPINT1 expression. Importantly, miR‐221/222 plays a key role in forming a favorable premetastatic niche (PMN) that leads to the aggressive nature of CRC, which was further shown through in vivo studies. Overall, our results show that exosomal miR‐221/222 promotes CRC progression and may serve as a novel prognostic marker and therapeutic target for CRC with LM.

Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis

“… 196 C19MC miRNAs are implicated in cancers and can be transferred to distant sites through exosomes. 197 , 198 Multiple exosome-delivered cargoes such as CD44v6/C1QBP complex (to promote fibrosis), 199 EGFR (to activate HGF), 200 miR-221/222 (from colorectal cancer), 201 ADAM-17(to activate E-cadherin cleavage), 202 ENO1 (to promote α6β4 integrin), precondition the liver metastatic niche to promote metastasis from various type of primary tumors (Fig. 4 ).…”

Micro-RNAs Predict Response to Systemic Treatments in Metastatic Renal Cell Carcinoma Patients: Results from a Systematic Review of the Literature

“…In our case, for example, some miRNAs were reported to be differentially expressed in various kinds of cancers. In fact, the deregulation of miR-221 was observed in several different malignancies, such as leukemia [ 30 ], as well as in colorectal [ 31 ], bladder, prostate, and kidney cancers [ 32 ]. These small molecules play key roles in the regulation of several pathways.…”

Implication of microRNAs in Carcinogenesis with Emphasis on Hematological Malignancies and Clinical Translation

“…In MM patients, down-regulation of four exosomal miRNAs (miR-5a-5p, miR-16-5p, miR-17-5p and miR-20a-5p) was registered in the bortezomib resistance group [ 207 ], and high levels of exosomal miR-1305 indicated poor OS [ 213 ]. MiR-221 and miR-222 secreted by CRC cells are implicated in the formation of a hospitable metastatic environment in the liver [ 214 ].…”