It is increasingly clear that hepatocellular carcinoma (HCC) has a distinct microRNA (miRNA) expression profile that is involved in malignancy; however, little is known about how functional miRNA modulates the metastasis of hepatitis B virus (HBV)-related HCC (HBV-HCC). In the present study, we demonstrate that the levels of miRNA-143 (miR-143) are dramatically increased in metastatic HBV-HCC of both p21-HBx transgenic mice and HCC patients. Moreover, we show that overexpression of this miRNA is transcribed by nuclear factor kappa B (NF-κB) and favors liver tumor cell invasive and metastatic behavior. Intratumoral administration of miR-143 shows that high levels of miR-143 can significantly promote HCC metastasis in an athymic nude mouse model. An in vivo study that used p21-HBx transgenic mice also showed that local liver metastasis and distant lung metastasis are significantly inhibited by blocking miR-143. Additionally, fibronectin type III domain containing 3B (FNDC3B), which regulates cell motility, was identified as the direct and functional target of miR-143 both in vivo and in vitro. Conclusion: Up-regulation of miR-143 expression transcribed by NF-κB in HBV-HCC promotes cancer cell invasion/migration and tumor metastasis by repression of FNDC3B expression. The present study provides a better understanding of the specificity of the biological behavior and thus may be helpful in developing an effective treatment against HBV-HCC. (HEPATOLOGY 2009.)

Hepatocellular carcinoma (HCC) is the 5th most common cancer in the world and accounts for more than 90% of human liver cancers. Hundreds of thousands of deaths result from HCC worldwide every year, and as many as 90% of these cancer-associated deaths are related to metastasis.¹ x 1 Jemal, A., Bray, F., Center, M.M. et al. Global cancer statistics. CA Cancer J Clin. 2011; 61: 69–90 Google Scholar See all References

Cancer stem cells (CSCs) are thought to drive uncontrolled tumor growth, and the existence of CSCs has recently been proven by direct experimental evidence, including tracing cell lineages within a growing tumor. However, CSCs must be analyzed in additional cancer types. Cancer stem cell-like cells (CSCLCs) are a good alternative system for the study of CSCs, which hold great promise for clinical applications. OCT4, NANOG, and SOX2 are three basic transcription factors that are expressed in both CSCLCs and embryonic stem cells (ESCs). These transcription factors play critical roles in maintaining the pluripotence and self-renewal characteristics of CSCLCs and ESCs. In this review, we discuss the aberrant expression, isoforms, and pseudogenes of OCT4, NANOG, and SOX2 in the CSCLC niche, which contribute to the major differences between CSCLCs and ESCs. We also highlight an anticancer therapy that involves killing specific cancer cells directly by repressing the expression of OCT4, NANOG, or SOX2. Importantly, OCT4, NANOG, and SOX2 provide great promise for clinical applications because reducing their expression or blocking the pathways in which they function may inhibit tumor growth and turn-off the cancer "switch." In the future, a clear understanding of transcription factor regulation will be essential for elucidating the roles of OCT4, NANOG, and SOX2 in tumorigenesis, as well as exploring their use for diagnostic and therapeutic purposes.

Purpose: Portal vein tumor thrombus (PVTT) is a major complication of hepatocellular carcinoma (HCC) and is associated with poor survival. Long noncoding RNAs (lncRNA) contribute to HCC metastasis, but whether and how lncRNAs affect PVTT development remains unclear. In the present study, a novel highly expressed lncRNA (ICAM-1–related, ICR) was identified in ICAM-1⁺ cancer stem cells (CSC) in HCC. This lncRNA regulated CSC properties and contributed to PVTT development. Experimental Design: We used microarray and bioinformatics analyses to identify differentially expressed lncRNAs. Real-time PCR and Western blotting were used to assess gene expression in cell lines and tumors. Sphere formation assays were performed to investigate stem cell properties of tumor cells in vitro. Retrospective and prospective studies were used to investigate the relationship between ICR expression and clinical outcomes. Results: Compared with the corresponding primary tumors, PVTT expressed different lncRNAs and mRNAs, including the upregulated lncRNA ICR and ICAM-1. ICR regulated ICAM-1 expression by increasing the stability of its mRNA through RNA duplex formation, which modulated the CSC properties of ICAM-1⁺ HCC cells. ICR transcription in ICAM-1⁺ HCC cells was regulated by Nanog, and inhibition of ICR in situ significantly reduced ICAM-1 expression and ICAM-1⁺ HCC cells in tumors in vivo. Moreover, elevated ICR and ICAM-1 expression in tumors was correlated with PVTT development and poor clinical outcomes. Conclusions: Our study demonstrates that ICR specifically regulates CSC properties of ICAM-1⁺ HCC cells and that ICR contributes to PVTT development. Therefore, ICR may be a promising target for HCC therapy. Clin Cancer Res; 22(8); 2041–50. ©2015 AACR.

Splicing factor 3b subunit 4 (SF3B4) is a splicing factor and potential oncogene in hepatocellular carcinoma (HCC); however, its regulatory mechanism is yet unclear. We aimed to determine the role of SF3B4 in HCC and the underlying mechanism. To investigate the association between alternative splicing events and miRNAs, putative miRNAs were screened using TargetScan. Expression levels of and prognostic information for SF3B4 and miRNAs were determined based on public genomic data and clinical samples. Then, we examined the possible roles of SF3B4 and miRNA-133b in HCC cells and a xenograft mouse model. Pearson correlation analysis and in vitro experiments verified SF3B4 as a miRNA-133b target. Protein levels of key targets from the SF3B4 signaling pathway were estimated using western blotting. The expression of SF3B4 was upregulated in HCC tissues and cell lines whereas, the expression of miRNA-133b was downregulated. MiRNA-133b negatively regulated the expression of SF3B4. Effects of SF3B4 overexpression were partially abolished by miRNA-133b mimics, confirming that SF3B4 is a target of miRNA-133b. Moreover, molecules associated with SF3B4, including KLF4, KIP1, and SNAI2, were also modulated by miRNA-133b. SF3B4 plays a crucial role in HCC and is negatively regulated by miRNA-133b. The miRNA-133b/ SF3B4 axis may serve as a new therapeutic target for HCC treatment. FUND: China National Funds for Distinguished Young Scientists (No.81425019), the State Key Program of National Natural Science Foundation of China (No.81730076), Shanghai Science and Technology Committee Program (No.18XD1405300) and Specially-Appointed Professor Fund of Shanghai (GZ2015009). China National Funds for National Natural Science Fund (No.81672899).

The universal expression of various non-coding RNAs (ncRNAs) is now considered the main feature of organisms' genomes. Many regions in the genome are transcribed but not annotated to encode proteins, yet contain small open reading frames (smORFs). A widely accepted opinion is that a vast majority of ncRNAs are not further translated. However, increasing evidence underlines a series of intriguing translational events from the ncRNAs, which were previously considered to lack coding potential. Recent studies also suggest that products derived from such novel translational events display important regulatory functions in many fundamental biological and pathological processes. Here we give a critical review on the potential coding capacity of ncRNAs, in particular, about what is known and unknown in this emerging area. We also discuss the possible underlying coding mechanisms of these extraordinary ncRNAs and possible roles of peptides or proteins derived from the ncRNAs in disease development and theranostics. Our review offers an extensive resource for studying the biology of ncRNAs and sheds light into the use of ncRNAs and their corresponding peptides or proteins for disease diagnosis and therapy.