| Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer worldwide, with more than 780,000 new cases and around 745,000 deaths attributed to HCC each year, making it the third most common cause of death from cancer. Liver transplantation and tumor resection are potentially curative options for patients with HCC, but unfortunately, most patients present with advanced-stage disease and are not eligible for these surgical therapies. HCC is also known for its spread, metastases and high rate of recurrence. Most studies reported a five-year survival rate of less than 30%. Hepatocarcinogenesis has often been described as a multistep process involving a number of genetic alterations eventually leading to the malignant transformation of the hepatocytes. Despite significant advances in diagnosis and management, the biology of HCC remains poorly understood mainly because of the complex genomic landscape of this tumor type. Hence, there is an urgent need to decipher the molecular pathways involved in HCC progression in order to identify biomarkers for early detection and develop new rational targeted therapeutic strategies.The pervasive view of gene regulation in biology has been mostly concentrated in protein-coding genes. However, with the advance of high-resolution microarray and massively parallel sequencing technology, it has been well accepted that at least 90% of the human genome is actively transcribed into non-coding RNAs. long noncoding RNAs (lncRNAs), mRNA-like polyadenylated transcripts ranging in length from 200 nucleotides up to 100 kb, that lack of coding protein function, are poorly conserved and capable to regulate gene expression at various levels, including chromatin modification, transcription and post-transcriptional processing. It is becoming evident that lncRNAs may be an important class of pervasive genes involved in carcinogenesis and metastasis.By high-throughput screening with microarray and proteomics combined with bioinformatics analysis and molecular biological techniques, the present investigation indicated that lncRNA hoxd-asl played a critical role in the development and metastasis of HCC. Its biological function and regulation mechanisms are concluded as follows.First, lncRNA hoxd-asl was significantly up-regulation in HCC and was closely related to the prognosis and survival rate of liver cancer patients. Through lncRNAs microarray profile, we found a novel lncRNA hoxd-asl, which was abnormally overexpression in HCC and many epithelial tumors, which indicated that hoxd-as1 might be involved in the development of HCC. Meanwhile, the expression of hoxd-asl was also upregulated in metastatic liver cancer which suggested that it was not only involved in the development of HCC, but also closely related to the metastasis of HCC. In addition, we found that patients with hoxd-as1 high expression tumors had an increasing risk of recurrence and significantly reduced overall postoperative survival. The results indicated that its expression may be used as a novel prognostic biomarker of HCC.Second, hoxd-as1 promotes tumor invasion and metastasis. By using gain of function and lose of function in vitro and in vivo, we found that hoxd-as1 can promote cell proliferation and inhibit apoptosis. In addition, we discovered that hoxd-as1 also can modulate migration and invasion of cancer cells. Meanwhile, it was also found that hoxd-as1 can significantly promote the development of liver cancer in nude mice by subcutaneous tumor formation and orthotopic tumor model, we also discovered that hoxd-as1 can significantly promote the metastasis by tail vein xenograft.Third, the mechanisms of hoxd-as1 in the development and metastasis of liver cancer were identified. Through our research, it was found that by specifically combining with polycomb protein suz12, hoxd-as1 can influence the G protein signaling pathways by regulating the rgs3 in epigenetic level and promoting the histone acetylation level of it, thereby inhibit the expression of RGS3 and promote the expression of ras gene, then activate the mek, and erk signaling pathway, and finally promote the development of liver cancer. In the mean time, we found that hoxd-as1 could compete endogenous RNA miR-19a, thus lifting the suppression of its target gene rap2a, which can activate the phosphorylated of Akt and promote the metastasis of liver cancer.In conclusion, a novel lncRNA, hoxd-as1, was discovered and identified to be closely related to the development and metastasis of HCC. The present investigation provides new candidate biomarkers for the early diagnosis and prognosis of liver cancer and may also provides new ideas and potential targets for personalized targeted therapy for clinical liver cancer patients. |
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