Comprehensive identification of somatic structural variations (SVs) and understanding their mutational mechanisms in cancer might contribute to understanding biological differences and help to identify new therapeutic targets. Unfortunately, characterization of complex SVs across the whole genome and the mutational mechanisms underlying esophageal squamous cell carcinoma (ESCC) is largely unclear. To define a comprehensive catalog of somatic SVs, affected target genes, and their underlying mechanisms in ESCC, we re-analyzed whole-genome sequencing (WGS) data from 31 ESCCs using Meerkat algorithm to predict somatic SVs and Patchwork to determine copy-number changes. We found deletions and translocations with NHEJ and alt-EJ signature as the dominant SV types, and 16% of deletions were complex deletions. SVs frequently led to disruption of cancer-associated genes (e.g., CDKN2A and NOTCH1) with different mutational mechanisms. Moreover, chromothripsis, kataegis, and breakage-fusion-bridge (BFB) were identified as contributing to locally mis-arranged chromosomes that occurred in 55% of ESCCs. These genomic catastrophes led to amplification of oncogene through chromothripsis-derived double-minute chromosome formation (e.g., FGFR1 and LETM2) or BFB-affected chromosomes (e.g., CCND1, EGFR, ERBB2, MMPs, and MYC), with approximately 30% of ESCCs harboring BFB-derived CCND1 amplification. Furthermore, analyses of copy-number alterations reveal high frequency of whole-genome duplication (WGD) and recurrent focal amplification of CDCA7 that might act as a potential oncogene in ESCC. Our findings reveal molecular defects such as chromothripsis and BFB in malignant transformation of ESCCs and demonstrate diverse models of SVs-derived target genes in ESCCs. These genome-wide SV profiles and their underlying mechanisms provide preventive, diagnostic, and therapeutic implications for ESCCs.

Emerging studies have revealed that microRNAs (miRNAs) are aberrantly expressed in hepatocellular carcinoma (HCC), and the dysregulation of miRNAs exerts crucial roles in the carcinogenesis and development of HCC. Therefore, elucidating the relationship between miRNAs and HCC progression is of great importance to develop novel therapeutic techniques and to improve the prognosis of patients with this malignancy. Recently, miR-548b-3p (miR-548b) has been demonstrated to be a cancer-associated miRNA in tongue squamous cell carcinoma and glioma. However, the expression and function of miR-548b in HCC remain poorly understood. In the present study, it was found that miR-548b is expressed at low levels in HCC tissues and cell lines. Decreased miR-548b expression was found to be positively associated with the clinical features of HCC, including the TNM stage and lymph node metastasis. Functional experiments revealed that upregulation of miR-548b expression decreased proliferation and invasion of HCC cells. Specificity protein 1 (SP1) was verified to be a direct target of miR-548b in HCC cells; as Spearman's correlation analysis identified miR-548b expression to be negatively correlated with that of SP1 expression in HCC tissue specimens. In addition, SP1 inhibition exhibited similar effects as miR-548b overexpression in HCC cells. SP1 reintroduction significantly reversed the suppressive effects of miR-548b upregulation on the proliferation and invasion of HCC cells. In conclusion, the results presented in the present study demonstrated that miR-548b may serve as a tumor suppressive miRNA that inhibits the proliferation and invasion of HCC cells by directly targeting SP1. Consequently, miR-548b can be exploited as a novel therapeutic target for treating patients with HCC in the future, but this needs to be investigated further.

Objective In the present investigation, we evaluated the effects of microRNA-365 (miR-365) on non-small-cell lung cancer (NSCLC) cell metastasis and invasion in patients with bone metastasis of lung cancer. Methods Blood samples from patients with NSCLC and healthy controls and the A549 adenocarcinoma cell line were included in this study. Quantitative real-time PCR and microarray were performed on blood samples. The MTT assay, luciferase reporter assay, Transwell assay, ELISA, and western blot were performed to evaluate expression of associated factors. Results Expression of miR-365 was reduced in patients with bone metastasis of NSCLC. Downregulation of miR-365 promoted cell growth, metastasis, and invasion of NSCLC. Upregulation of miR-365 reduced cell growth, metastasis, and invasion of NSCLC. Downregulation of miR-365 induced expression of NKX homeobox-1 (NKX2-1), epidermal growth factor receptor (EGFR), phosphoinositide-3-kinase (PI3K), and p-Akt proteins in an in vitro model of NSCLC. Inhibition of NKX2-1 reduced the effects of miR-365 on cell growth, metastasis, and invasion of NSCLC. Activation of EGFR reduced the effects of miR-365 on cell growth, metastasis, and invasion of NSCLC. Conclusions The study established that the serum miR-365 suppresses NSCLC cell metastasis and invasion in patients with bone metastasis of lung cancer via EGFR/PI3K through NKX2-1.

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