Abstract
MicroRNAs (miRNAs) often localize to chromosomal fragile sites and are associated with cancer. In this study, we screened for the aberrant and functional miRNAs in the regions of copy number alterations (CNAs) in hepatocellular carcinoma (HCC), and found that miR-135b was frequently amplified and upregulated in HCC tissues. The expression level of miR-135b was inversely correlated with the occurrence of tumor capsules. In addition, miR-135b promoted HCC cell migration and invasion in vitro and metastasis in vivo. The reversion-inducing-cysteine-rich protein with kazal motifs (RECK) and ecotropic viral integration site 5 (EVI5) were identified as the direct and functional targets of miR-135b in HCC. Furthermore, we observed that heat shock transcription factor 1 (HSF1) directly activated miR-135b expression, consequently enhancing HCC cell motility and invasiveness. The newly identified HSF1/miR-135b/RECK&EVI5 axis provides novel insight into the mechanisms of HCC metastasis, which may facilitate the development of new therapeutics against HCC.
Highlights
Hepatocellular carcinoma (HCC) accounts for 85–90% of primary liver cancers and is the third most common cause of cancer mortality[1]
MiR-135b is upregulated in hepatocellular carcinoma (HCC) and its expression is inversely correlated with tumor capsule occurrence
MiR-135b is upregulated in other types of cancers, including colorectal cancer (CRC)[18], non-small cell lung cancer[19], anaplastic larger cell lymphoma[20], and head and neck squamous cell carcinoma[21]
Summary
Hepatocellular carcinoma (HCC) accounts for 85–90% of primary liver cancers and is the third most common cause of cancer mortality[1]. HCC occurs within an established background of chronic liver disease and cirrhosis, with major risk factors being hepatitis B and C viruses, alcohol, aflatoxin B, and non-alcoholic fatty liver disease. Genomic instability is a hallmark of cancers, and recurrent chromosomal alterations often occur in tumors[2]. We previously identified 1241 recurrent regions of somatic copy number alterations (CNAs) in HCC primary tumors using a whole-genome Affymetrix SNP 6.0 array[3]. Several functional protein-coding genes, TRIM35, HEY1, SNRPE, MPZL1 and SERPINA5 were identified in these somatic CNAs[3,4,5]. It has been reported that many miRNAs in genomic fragile sites play vital roles in human cancer[6]
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