Conversion of primary liver cancer after targeted therapy for liver cancer combined with AFP-targeted CAR T-cell therapy: a case report.

Primary liver cancer (PLC) that originates in the liver is a malignant tumor with the worst prognosis. Hepatocellular carcinoma (HCC) is the most common type of PLC. Most PLC cases are diagnosed at advanced stages mainly due to their insidious onset and rapid progression. Patients with PLC undergo surgical intervention or localized treatment, but their survival is often affected by its high relapse rate. Medical treatment is the primary option for patients with liver cancer, especially with advanced extrahepatic metastases. Molecular targeted therapy exerts an anti-tumor effect by acting on various signaling pathways involved in molecular pathogenesis; however, high drug resistance and low therapeutic responsiveness of PLC to molecular targets challenge the treatment option. In recent years, after surgical intervention, radiotherapy, chemotherapy, and/or molecular targeted therapy, autologous cell immunotherapy has been adopted for PLC. As a typical autologous cell immunotherapy, CAR T-cell therapy uses genetically modified T cells to express tumor-specific chimeric antigen receptors (CARs). Its targeting ability, persistent nature, and tumor-killing function result in a significant impact on the treatment of hematological tumors. However, no breakthrough has happened in the research specific to the curation of lung cancer, liver cancer, breast cancer, and other common solid tumors. In this context, a combination of molecular targeted therapy and CAR T-cell therapy was used to treat a patient with advanced HCC to achieve a partial remission(PR) and facilitate further liver transplantation.

miR-200a-3p- and miR-181-5p-Mediated HOXB5 Upregulation Promotes HCC Progression by Transcriptional Activation of EGFR.

Background: Hepatocellular carcinoma (HCC) remains a worldwide burden. However, the mechanisms behind the malignant biological behavior of HCC remain unclear. The homeobox (HOX) family could act as either promoters or suppressors in different kinds of malignancies. Our study discovered the role of HOXB5 in regulating HCC progression. Methods: The HOXB5 expression was assessed by RT-PCR analysis in human HCC samples and cell lines. HOXB5 transcriptional regulation of the EGFR was verified by the luciferase reporter assay and chromatin immunoprecipitation experiment. The oncogenic role of HOXB5 in HCC progression was analyzed by CCK8, colony-forming, and transwell assays. Results: Upregulation of HOXB5 was found in human HCC, and was strongly correlated with HCC tumor size, tumor-nodule metastasis, TNM stage, and relatively unfavorable OS and DFS. Ectopic expression of HOXB5 promoted the capacity of cell growth and clonogenicity, while the inhibition of HOXB5 decreased the proliferation and clonogenicity potential in vitro by CCK8 and colony-forming assays. In addition, HOXB5 also promoted cell migration by transwell experiment. Mechanism studies elucidated that HOXB5 triggers HCC progression via direct transcriptional activation of EGFR. The upregulation of HOXB5 is regulated by miR-200a-3p and miR-181-5p. Transfection of miR-200a-3p and miR-181-5p mimics blocked the cell proliferation and migration regulated by HOXB5, while overexpression of the 3'-UTR mutant HOXB5 abolished the suppressive effect of miR-200a-3p and miR-181-5p, but not the wild-type HOXB5. Conclusion: HOXB5 is a promising prognostic factor in human HCC. Targeting miR-200a-3p and the miR-181-5p/HOXB5/EGFR signaling pathway may provide new options for the treatment strategies of HCC.

MicroRNA-455-3p functions as a tumor suppressor by targeting HDAC2 to regulate cell cycle in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers. MicroRNA has been studied more and more deeply and may become a new target for the treatment of HCC. Here, we investigated the role of miR-455-3p in HCC progression. Compared with non-tumor tissues and normal human hepatic cells, miR-455-3p expression was significantly downregulated in HCC tissues and cell lines. And overexpression of miR-455-3p inhibited cell proliferation and migration but promoted cell apoptosis in HCC cell lines HepG2 and Huh7. Mechanism studies displayed that miR-455-3p targeted HDAC2 and negatively regulated HDAC2 expression. Moreover, HDAC2 was highly expressed in HCC tissues and cell lines. Overexpression of HDAC2 reversed the inhibitory effects of miR-455-3p on cell proliferation, migration and cell cycle protein (CDK6 and cyclin D1) expression, and neutralized the promotion effects of miR-455-3p on cell apoptosis and the activation of p53 pathway. Furthermore, a p53 inhibitor Pifithrin-α (PFT-α) effectively abolished the effects of miR-455-3p on HCC cell behaviors. Additionally, the role of miR-455-3p in tumorigenesis was evaluated by using a mouse xenograft model, and the data showed that miR-455-3p suppressed tumor growth in vivo. In summary, our results suggested that miR-455-3p targeted HDAC2 to inhibit cell proliferation, migration and promote cell apoptosis via the activation of p53 pathway.

HIPK3 Circular RNA Promotes Metastases of HCC Through Sponging miR-338-3p to Induce ZEB2 Expression.

BACKGROUND: Upregulation of circHIPK3 has been observed in several kinds of malignancies. However, the mechanisms of circHIPK3 in HCC metastases remains unclear. We investigated the role and the mechanisms of circHIPK3 in the development of HCC. METHODS: HCC tissues and paired adjacent non-tumor tissues of surgical patients were used to evaluate circHIPK3 expression. A series of biological experiments had been taken to evaluate the pro-metastatic ability of circHIPK3 during HCC development in vitro and in vivo. The potential mechanisms of circHIPK3 in HCC development were identified by RT-qPCR, Western blot, RIP, and luciferase reporter assays. RESULTS: CircHIPK3 expression is significantly upregulated during HCC development. Overexpression of circHIPK3 promotes cell migration, invasion, and metastases in vitro and in vivo. CircHIPK3 promoted HCC metastases by sponging miR-338-3p to regulate EMT-associated proteins E-cadherin, vimentin, and ZEB2 expression. CONCLUSION: CircHIPK3 plays a regulatory role in metastatic HCC by sponging miR-338-3p to induce ZEB2 expression, thus promoting EMT procession.

The long noncoding RNA OTUD6B-AS1 enhances cell proliferation and the invasion of hepatocellular carcinoma cells through modulating GSKIP/Wnt/ß-catenin signalling via the sequestration of miR-664b-3p.

Ovarian tumour domain containing 6B antisense RNA1 (OTUD6B-AS1), a newly identified long noncoding RNA (lncRNA), has been reported as a key cancer-related lncRNA. However, the detailed relevance of OTUD6B-AS1 in hepatocellular carcinoma (HCC) remains undetermined. This study was designed to determine the functional significance and regulatory mechanism of OTUD6B-AS1 in HCC. We found that the expression of OTUD6B-AS1 was up-regulated in HCC tissues, and patients with high levels of OTUD6B-AS1 expression had shorter survival rates than those with low OTUD6B-AS1 expression. Elevated expression of the lncRNA was also found in multiple HCC cell lines and the silencing of OTUD6B-AS1 significantly decreased proliferation, colony formation and invasion. Correspondingly, OTUD6B-AS1 overexpression had the opposite effect on HCC cell invasion, colony formation and proliferation. Notably, OTUD6B-AS1 was identified as a molecular sponge of microRNA-664b-3p (miR-664b-3p). The down-regulation of miR-664b-3p was detected in HCC tissues and cell lines, and the up-regulation of miR-664b-3p repressed proliferation and invasion in HCC cells by targeting the glycogen synthase kinase-3ß interaction protein (GSKIP). Moreover, OTUD6B-AS1 knockdown or miR-664b-3p up-regulation exerted a suppressive effect on Wnt/ß-catenin signalling via the down-regulation of GSKIP. In addition, GSKIP overexpression markedly reversed OTUD6B-AS1 knockdown- or miR-664b-3p overexpression-induced antitumour effects in HCC. Further data confirmed that OTUD6B-AS1 knockdown exerted a tumour-inhibition role in HCC in vivo. Overall, these findings indicate that the lncRNA OTUD6B-AS1 accelerates the proliferation and invasion of HCC cells by enhancing GSKIP/Wnt/ß-catenin signalling via the sequestration of miR-664b-3p. Our study reveals a novel molecular mechanism, mediated by lncRNA OTUD6B-AS1, which may play a key role in regulating the progression of HCC.

ATDC promotes the growth and invasion of hepatocellular carcinoma cells by modulating GSK-3ß/Wnt/ß-catenin signalling.

Accumulating evidence has suggested that the ataxia telangiectasia group D complementing (ATDC) gene is an emerging cancer-related gene in multiple human cancer types. However, little is known about the role of ATDC in hepatocellular carcinoma (HCC). In this study, we aimed to investigate the expression level, biological function and underlying mechanism of ATDC in HCC. The expression of ATDC in HCC cells was detected by quantitative real-time polymerase chain reaction and western blot analysis. Cell growth was determined by cell counting kit-8 assay and colony formation assay. Cell invasion was assessed by Transwell invasion assay. The activation status of Wnt/ß-catenin signalling was evaluated by the luciferase reporter assay. Functional experiments showed that the silencing of ATDC expression significantly suppressed the growth and invasion of HCC cells, whereas the overexpression of ATDC promoted the growth and invasion of HCC cells in vitro. Moreover, we showed that ATDC overexpression promoted the phosphorylation of glycogen synthase kinase (GSK)-3ß and resulted in the activation of Wnt/ß-catenin signalling. Notably, the inhibition of GSK-3ß activity significantly abrogated the tumour suppressive effect of ATDC silencing, while the silencing of ß-catenin partially reversed the oncogenic effect of ATDC overexpression. Taken together, these findings reveal an oncogenic role of ATDC in HCC and show that the suppression of ATDC impedes the growth and invasion of HCC cells associated with the inactivation of Wnt/ß-catenin signalling. Our study suggests that ATDC may serve as a potential therapeutic target for HCC.

Mechanical Properties and Carbonation Durability of Engineered Cementitious Composites Reinforced by Polypropylene and Hydrophilic Polyvinyl Alcohol Fibers.

Herein, the mechanical properties and carbonation durability of engineered cementitious composites (ECC) were studied. For the cost-efficient utilization of ECC materials, different types of specimens were cast with polypropylene (PP) and hydrophilic polyvinyl alcohol (HPVA) fibers. The compressive strength, Poisson’s ratio, strength-deflection curves, cracking/post-cracking strength, impact index, and tensile strain-stress curves of two types of ECC materials, with differing fiber contents of 0 vol %, 1 vol %, 1.5 vol %, and 2 vol %, were investigated with the use of compressive tests, four-point bending tests, drop-weight tests, and uniaxial tensile tests. In addition, the matrix microstructure and failure morphology of the fiber in the ECC materials were studied by scanning electron microscopy (SEM) analysis. Furthermore, carbonation tests and characterization of steel corrosion after carbonization were employed to study durability resistance. The results indicated that for both PP fiber- and HPVA fiber-reinforced ECCs, the compressive strength first increases and then decreases as fiber content increases from 0 vol % to 2 vol %, reaching a maximum at 1 vol % fiber content. The bending strength, deformation capacity, and impact resistance show significant improvement with increasing fiber content. The ECC material reinforced with 2 vol % PP fiber shows superior carbonized durability with a maximum carbonation depth of only 0.8 mm.