Hepatocytes are epithelial cells with highly specialized polarity. The disorder and loss of hepatocyte polarity leads to a weakness of cell adhesion and connection, the induction of epithelial–mesenchymal transition, and eventually the occurrence of hepatocellular carcinoma (HCC). Cluster of differentiation 147 (CD147), a tumor‐related glycoprotein, promotes epithelial–mesenchymal transition and the invasion of HCC. However, the function of CD147 in hepatocyte depolarization is unknown. Here we identified that CD147 was basolaterally polarized in hepatocyte membrane of liver tissues and HepG2 cells. CD147 not only promoted transforming growth factor‐β1–mediated hepatocyte polarity loss but also directly induced endocytosis and down‐regulation of E‐cadherin which contributed to hepatocyte depolarization. Overexpression of CD147 induced Src activation and subsequently recruited ubiquitin ligase Hakai for E‐cadherin ubiquitination and lysosomal degradation, leading to decreases of partitioning defective 3 expression and β‐catenin nuclear translocation. This signal transduction was initiated by competitive binding of CD147 with integrin β1 that interrupted the interaction between the Arg‐Gly‐Asp motif of fibronectin and integrin β1. The specific antibodies targeting integrin α5 and β1 reversed the decrease of E‐cadherin and partitioning defective 3 levels induced by CD147 overexpression. In human liver tissues, CD147 polarity rates significantly declined from liver cirrhosis (71.4%) to HCC (10.4%). CD147‐polarized localization negatively correlated with Child‐Pugh scores in human liver cirrhosis (r = –0.6092, P < 0.0001) and positively correlated with differentiation grades in HCC (r = 0.2060, P = 0.004). HCC patients with CD147‐polarized localization had significantly better overall survival than patients with CD147 nonpolarity (P = 0.021). Conclusion: The ectopic CD147‐polarized distribution on basolateral membrane promotes hepatocyte depolarization by activation of the CD147–integrin α5β1–E‐cadherin ubiquitination–partitioning defective 3 decrease and β‐catenin translocation signaling cascade, replenishing a molecular pathway in hepatic carcinogenesis. (Hepatology 2018;68:317‐332).
The etiology of cancer includes aberrant cellular homeostasis where a compromised RNA regulatory network is a prominent contributing factor. In particular, noncoding RNAs including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) were recently shown to play important roles in the initiation, progression, and metastasis of human cancers. Nonetheless, a mechanistic understanding of noncoding RNA functions in lung squamous cell carcinoma (LUSC) is lacking. To fill this critical gap in knowledge, we obtained mRNA, miRNA, and lncRNA expression data on patients with LUSC from the updated Cancer Genome Atlas (TCGA) database (2016). We successfully identified 3,366 mRNAs, 79 miRNAs, and 151 lncRNAs as key contributing factors of a high risk of LUSC. Furthermore, we hypothesized that the lncRNA–miRNA–mRNA regulatory axis positively correlates with LUSC and constructed a competitive endogenous RNA (ceRNA) network of LUSC by targeting interrelations with significantly aberrant expression data between miRNA and mRNA or lncRNA. Six ceRNAs (PLAU, miR-31-5p, miR-455-3p, FAM83A-AS1, MIR31HG, and MIR99AHG) significantly correlated with survival (P < 0.05). Finally, real-time quantitative PCR analysis showed that PLAU is significantly upregulated in SK-MES-1 cells compared with 16-BBE-T cells. Taken together, our findings represent new knowledge for a better understanding the ceRNA network in LUSC biology and pave the way to improved diagnosis and prognosis of LUSC.
Motivation: Complex diseases are generally thought to be under the influence of one or more mutated risk genes as well as genetic and environmental factors. Many traditional methods have been developed to identify susceptibility genes assuming a single-gene disease model ('single-locus methods'). Pathway-based approaches, combined with traditional methods, consider the joint effects of genetic factor and biologic network context. With the accumulation of high-throughput SNP datasets and human biologic pathways, it becomes feasible to search for risk pathways associated with complex diseases using bioinformatics methods. By analyzing the contribution of genetic factor and biologic network context in KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, we proposed an approach to prioritize risk pathways for complex diseases: Prioritizing Risk Pathways fusing SNPs and pathways (PRP). A risk-scoring (RS) measurement was used to prioritize risk biologic pathways. This could help to demonstrate the pathogenesis of complex diseases from a new perspective and provide new hypotheses. We introduced this approach to five complex diseases and found that these five diseases not only share common risk pathways, but also have their specific risk pathways, which is verified by literature retrieval. Availability: Genotype frequencies of five case-control samples were downloaded from the WTCCC online system and the address is https://www.wtccc.org.uk/info/access_to_data_samples.shtml
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