Hepatocellular carcinoma (HCC) is one of the most common malignancies and has an unfavorable prognosis. The hepatitis B virus X (HBx) protein has been reported to be closely associated with hepatocarcinogenesis. Meanwhile, emerging evidence has indicated that long noncoding RNAs (lncRNAs) are involved in the pathogenesis and progression of cancers. Our previous investigation has demonstrated that HBx could promote HCC by regulating the expression levels of various lncRNAs. In this study, we identified an lncRNA, lncRNA-TCONS_00006195 (termed lncRNA-6195), which was downregulated in HBV-related HCC tissues compared with its expression in adjacent noncancerous hepatic tissues. Clinical data showed that a low level of lncRNA-6195 was correlated with a high Edmondson–Steiner grade of the tumor and a poor prognosis in HCC patients. Furthermore, lncRNA-6195 acted as a tumor repressor in the development of hepatitis B-related HCC, inhibiting HCC cell proliferation in vitro and in vivo. Moreover, lncRNA-6195 could combine with α-enolase (ENO1) and repress its enzymatic activity, thus further inhibiting the energy metabolism in HCC cells. Our results suggest that lncRNA-6195 represses the growth of HCC by inhibiting the enzymatic activity of ENO1. These findings provide new insights into the mechanisms underlying the lncRNA involvement in hepatocarcinogenesis and can serve as a basis for the development of novel strategies to hinder HCC.
Transcription factor PAX8 expression is upregulated in several types of cancers. However, little is known about the function of PAX8 in the progression of hepatoma and its regulatory mechanisms. Here, we show that PAX8 silencing inhibits the proliferation and clonogenicity of hepatoma cells and its growth in vivo. The HBV X protein (HBx) does not directly interacts, but stabilizes PAX8 by inhibiting proteasome-dependent ubiquitination and degradation. Furthermore, the E3 ubiquitin ligase complex component Skp2 through its LRR domain directly interacts with the Prd domain of PAX8 and targets PAX8 by recognizing its lysine 275 for ubiquitination and degradation in hepatoma cells. In addition, HBx directly interacts and is colocalized with Skp2 to inhibit its recognition and subsequent ubiquitination and degradation of PAX8 in hepatoma cells. Moreover, HBx upregulates the expression and phosphorylation of Aurora A, a serine-threonine kinase, which interacts with and phosphorylates PAX8 at S209 and T277, compromising the Skp2-recognized PAX8 ubiquitination and destabilization. Thus, HBx stabilizes PAX8 protein by inhibiting the Skp2 targeted PAX8 ubiquitination and enhancing the Aurora A-mediated its phosphorylation, contributing to the progression of hepatoma. Our findings suggest that PAX8 may a new target for design of therapies and uncover new insights into the pathogenesis of hepatoma.
LGR5 and LGR6 mark epithelial stem cells in many niches including the ovarian surface and fallopian tube epithelia from which ovarian cancer arises. Human ovarian cancers express these receptors at high levels and express one of their ligands, RSPO1, at levels uniquely higher than all other tumor types except mesothelioma. Reasoning that these receptors are also important to tumor stem cells, arming the LGR binding domain of RSPO1 with a cytotoxin may permit depletion of the tumor stem cells. The Fu1-Fu2 receptor binding domain of RSPO1 (R1FF), containing a sortase recognition sequence at the C-terminal end, was produced in bacteria and a single molecule of MMAE was attached to each R1FF through a val-cit-PAB linker using the sortase reaction, thus producing a homogeneous population of armed molecules. R1FF-MMAE demonstrated (1) selective LGR-dependent binding, uptake, and cytotoxicity; (2) low nM cytotoxicity to multiple types of human tumor cell lines in vitro; (3) favorable plasma pharmacokinetic properties when administered iv with an elimination half-life of 27.8 h; (4) favorable absorption from the peritoneal cavity; and (5) therapeutic activity in aggressive xenograft models of ovarian cancer in the absence of any weight loss or other adverse events. These results demonstrate that the Fu1-Fu2 domain of RSPO1 can be exploited to deliver a potent cytotoxin to tumor cells that express the LGR4-6 family of stem cell receptors.
Hepatic stellate cell (HSC) activation is a critical event in the development of hepatic fibrosis and hepatocellular carcinoma (HCC). By the release of soluble cytokines, chemokines, and chemotaxis, HSCs affect HCC cell phenotypes through a complex tumor microenvironment. In this study, weighted gene co-expression network analysis (WGCNA) was used to identify the TGFβ signaling pathway as a key signaling pathway in Hep3B cells cultured in HSC conditioned medium. MIR4435-2HG is a hub lncRNA associated with the TGFβ signaling pathway and HSC activation. HSC-condition medium (CM) culture induced HCC cell malignant behaviors, which were partially reversed by MIR4435-2HG silencing. miR-506-3p directly bound to MIR4435-2HG and the 3′UTR of TGFB1. Similarly, overexpression of miR-506-3p also attenuated HSC-CM-induced malignant behavior of HCC cells. In HSC-CM cultured HCC cells, the effects of MIR4435-2HG knockdown on TGFB1 expression and HCC cell phenotypes were partially reversed by miR-506-3p inhibition. HSCs affected HCC cell phenotypes by releasing CXCL1. In an orthotopic xenotransplanted tumor model of HCC cells plus HSCs in mice, CXCR2 knockdown in HCC cells significantly inhibited tumorigenesis, which was partially reversed by MIR4435-2HG overexpression in HCC cells.In HCC tissue samples, the levels of CXCL1, TGF-β1, and MIR4435-2HG were upregulated, while miR-506-3p expression was downregulated. In conclusion, HSCreleased CXCL1 aggravated HCC cell malignant behaviors through the MIR4435-2HG/miR-506-3p/TGFB1 axis. In addition to CXCL1, the MIR4435-2HG/miR-506-3p/ TGFB1 axis might also be the underlying target for HCC therapy.
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