Colorectal cancer (CRC) is one of the most common malignancies and the 2nd most common cause of cancer deaths worldwide [ 1 , 2 ]. Surgical treatment with or without adjuvant radiation and chemotherapy treatments based on growth stages have been recommended according to current guidelines. However , you may still find patients with early surgery suffering from metastases, especially liver organ metastases, which can finally result in death [ 3 ]. Such as other solid cancers, the development of CRC is a multistep development involving the activation of oncogenes and inactivation of growth suppressor genes, which will affect all aspects of tumorigenicity associated with CRC, such as cell proliferation, apoptosis, invasion, and metastasis [ 4 ]. Because of the disease complexity, the specific molecular hereditary and epigenetic alterations of CRC remain largely not known.
MicroRNAs (miRNAs) are little (19– 25 nucleotides), noncoding, regulatory RNAs that can adversely regulate gene expression by complementary base pairing using the 3′ -untranslated region (UTR) of target messenger RNAs (mRNAs), leading to their degradation or repression of mRNA translation [ 5 , 6 ]. Abnormal expression of miRNAs will be suggested to be associated with various human disorders, including malignancy, indicating that they play a critical role in the molecular system of cancer pathogenesis and progression [ 7 ].
The gene encoding microRNA-140-5p (miR-140) is located in chromosome 16. It was first found as a cartilage-specific expression microRNA. Wienholds et al. [ 8 ] and Tuddenham et al. [ 9 ] documented that miR-140 was specifically expressed in cartilage tissue of zebrafish and mouse embryos, and later the downregulation was shown to play a critical role in the pathogenesis of osteoarthritis (OA) [ 10 – 12 ]. Importantly, several latest studies have revealed the functions of miR-140 in tumorigenesis. The results from our group showed that ectopic expression associated with miR-140 in human osteosarcoma and CRC cells may induce cell cycle arrest and inhibit cell expansion, in part through the suppression of histone deacetylase 4 (HDAC4) [ 13 ]. In hepatocellular carcinoma (HCC), miR-140 has been found to target TGFBRI and FGF9, and its overexpression can suppress HCC growth and metastasis [ 14 ]. Within non-small cell lung cancer (NSCLC), miR-140 can focus on IGF1R and monocyte to macrophage differentiation-associated (MMD) in order to inhibit tumor growth and metastasis [ 15 ]. miR-140 inhibited esophageal cancer cell invasion by targeting slug and the subsequent epithelial-mesenchymal transition (EMT) process [ 16 ]. Additionally , several studies indicated that downregulation of miR-140 can promote cancer stem cell (CSC) formation within breast cancer and CRC [ 17 – 21 ]. However , some contradictions still exist concerning the role of miR-140 in tumor development. Malzkorn et al. [ 22 ] reported that will miR-140 is one of the increased microRNA candidates in glioma development from grade II to grade IV. Gü llü et al. [ 23 ] also found that miR-140 is overexpressed in the invasive ductal breast cancer tissues plus lymph node-positive samples. Based on the above studies, we plan to investigate the impact and mechanism of miR-140 upon CRC progression.
A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family is really a type of newly discovered, zinc-dependent secreted proteinase consisting of nineteen members that share the metalloproteinase domain with matrix metalloproteinases (MMPs) [ 24 ]. Among ADAMTSs, ADAMTS5 (aggrecanase-2) is well known for its importance in cartilage destruction [ 24 ]. Recently, increasing evidence suggests that ADAMTS5 is involved in malignancy development and progression. Nakada et al. [ 25 ] reported that ADAMTS5 is upregulated in human being glioblastoma compared to the normal brain tissues and its overexpression may enhance the invasive capacity of glioblastoma cells through matrigel which contains brevican, a substrate for ADAMTS5. One more study showed that higher mRNA expression of ADAMTS5 is found in the metastatic foci of head and neck cancer when compared with their corresponding primary tumors as well as normal tissues [ 26 ]. Filou et al. [ 27 ] documented that ADAMTS5 is the main type of aggrecanase expressed within the laryngeal squamous cell carcinoma (LSCC) and presents the stage-related increase. A more recent study reported that miR-144/451 inhibits breast cancer and head and neck squamous cell carcinoma (HNSCC) metastasis by targeting ADAMTS5 and ADAM10, and the overexpression of these two proteins being significantly associated with lymph client metastasis and pathological grade [ 28 ].
Insulin-like growth factor (IGF)-binding proteins (IGFBPs) are important regulators of the IGF signaling pathway which contains six members [ 29 ]. IGFBP5, the most conserved person in the IGFBPs in all vertebrates, has been found to play a task not only in the physical processes, such as cell growth, demise, and motility, but also in the pathologic processes such as malignancy development and metastasis [ 30 ]. IGFBP5 promotes prostate cancer growth in vitro and in vivo [ 31 – 33 ]. The plasma levels of IGFBP5 are 1 . 5-fold increased in breast cancer-bearing mice than in nontumor-bearing mice and therefore are positively correlated with the tumor size [ 34 ]. In the rat colon cancer model, IGFBP5 is among the most upregulated gene by microarray gene expression analysis [ 35 ]. Hao et al. [ 36 ] reported the expression of IGFBP5 is increased in breast malignancies with axillary lymph node involvement and lymph client metastatic tissues compared with primary breast cancer samples. Wang ainsi que al. [ 37 ] also found that IGFBP5 much more highly expressed in T1 invasive breast cancer than in regular breast epithelium. Moreover, T1N1 breast cancers are more likely to possess moderate and strong positive staining for IGFBP5 compared to T1N0 cancers.
These information suggest that ADAMTS5 and IGFBP5 may promote the tumorigenesis and cancer progression. Very interestingly, Miyaki et ‘s. [ 10 ] and Tardif et al. [ 38 ] have experimentally confirmed that ADAMTS5 plus IGFBP5 are the direct targets of miR-140 in HEK293T cells and human OA chondrocytes, respectively. Our earlier study has shown that miR-140 inhibits human osteosarcoma plus CRC cell growth and is also involved in the chemoresistance to methotrexate and 5-fluorouracil (5-FU) [ 13 ]. In the current study, we all investigated the suppressive role of miR-140 in CRC progression and the correlation with downregulating ADAMTS5 and IGFBP5.