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The N6-methyladenosine (m6A) RNA methyltransferase METTL16 is an emerging player in RNA modification landscape and responsible for the deposition of m6A in a few transcripts. AURKA (aurora kinase A) has been confirmed as an oncogene in cancer development including hepatocellular carcinoma (HCC). Nevertheless, it remains unclear whether METTL16 mediated m6A modification of lncRNAs can regulate AURKA activation in cancer progression. Here we aimed to investigate the functional links between lncRNAs and the m6A modification in AURKA signaling and HCC progression. Here we show that LncRNA TIALD (transcript that induced AURKA Lysosomal degradation) was down-regulated in HCC tissues by METTL16 mediated m6A methylation to facilitate its RNA degradation, and correlates with poor prognosis. Functional assays reveal that TIALD inhibits HCC metastasis both in vitro and in vivo. Mechanistically, TIALD directly interacts with AURKA and facilitate its degradation through the lysosomal pathway to inhibited EMT and metastasis of HCC. AURKA’s specific inhibitor alisertib exerts effective therapeutic effect on liver cancer with low TIALD expression, which mightprovide a new insight into HCC therapy. Our study uncovers a negative functional loop of METTL16-TIALD-AURKA axis, and identifies a new mechanism for METTL16 mediated m6A-induced decay of TIALD on AURKA signaling in HCC progression, which may provide potential prognostic and therapeutic targets for HCC.

Yue Zhong,1– 3 Yong Yang,2,4 Lei He,2,4 Yang Zhou,2 Niangmei Cheng,2 Geng Chen,2,4 Bixing Zhao,2,4 Yingchao Wang,2,4 Gaoxiong Wang,5,6 Xiaolong Liu2– 4 1College of Life Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, People’s Republic of China; 2The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350025, People’s Republic of China; 3Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, People’s Republic of China; 4College of Biological Science and Engineering and Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian, 350116, People’s Republic of China; 5Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362001, People’s Republic of China; 6Quanzhou Maternal and Child Health Hospital, Children’s Hospital, Quanzhou, Fujian, 362017, People’s Republic of ChinaCorrespondence: Yingchao WangThe United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao, Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of ChinaEmail yingchaowang@live.comGaoxiong WangDepartment of Hepatobiliary Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362001, People’s Republic of ChinaEmail wanggaoxiong2013@163.comBackground: The aberrant expressions of lncRNAs have been frequently demonstrated to be closely associated with the prognosis of patients in many cancer types including hepatocellular carcinoma (HCC). Integration of these lncRNAs might provide accurate evaluation of HCC. Therefore, this study aims to develop a novel prognostic evaluation model based on the expression of lncRNAs to predict the survival of HCC patients, postoperatively.Patients and Methods: RNA sequencing (RNA-seq) analysis was performed for 61 HCC patients (training cohort) to screen prognosis-associated lncRNAs with univariate Cox regression and Log rank test analyses. Multivariate Cox regression analysis was then applied to establish the final model, which was further verified in a validation cohort (n=191). Moreover, performance of the mode was assessed with time-dependent receiver operating characteristic curve (tdROC), Harrell’s c-index, and Gönen & Heller’s K.Results: After a serial statistical computation, a novel risk scoring model consisting of four lncRNAs and TNM staging was established, which could successfully divide the HCC patients into low-risk and high-risk groups with significantly different OS and RFS in both training and validation cohorts. tdROC analysis showed that this model achieved a high performance in predicting OS and 2-year RFS in both cohorts. Gene Set Enrichment Analysis revealed that HCC tumor tissues with high-risk score have stronger capacities in immune escape and resistance to treatment.Conclusion: We successfully established a novel prognostic evaluation model, which exhibited reliable capacity in predicting the OS and early recurrence of HCC patients with relatively higher accuracy.Keywords: hepatocellular carcinoma, long noncoding RNA, risk score, prognosis, survival

Circular RNAs (circRNAs) are a class of highly stable and closed-loop noncoding RNA that are involved in the occurrence and development of hepatocellular carcinoma (HCC). However, little is known about the therapeutic role of circRNAs in HCC. We found that high circ_0058051 expression was negatively correlated with the prognosis of HCC patients. Circ_0058051 knockdown attenuated the proliferation and colony formation, meanwhile inhibited migration of HCC cells. Circ_0058051 may be used as a target for HCC gene therapy. We synthesized a novel small interfering RNA (siRNA) delivery system, PEG-PCL-PEI-C14-SPIONs (PPPCSs), based on superparamagnetic iron oxide nanoparticles (SPIONs). PPPCSs protected the siRNA of circ_0058051 from degradation in serum and effectively delivered siRNA into SMMC-7721 cells. Meanwhile, intravenous injection of the PPPCSs/siRNA complex could inhibit tumor growth in the subcutaneous tumor model. In addition, the nanocomposite is not toxic to the organs of nude mice. The above results show that PPPCSs/si-circ_0058051 complex may provide a novel and promising method of HCC treatment. Graphical abstract

Aberrant expression of long noncoding RNAs (lncRNAs) has been involved in progression of various human tumors including hepatocellular carcinoma (HCC). However, the role of lncRNAs in HCC has not fully explained. Our study aimed to investigate the biological function and potential molecular mechanism of Lnc-PAL2G4A-4 in HCC. Our study showed that Lnc-PLA2G4A-4 was significantly up-regulated in HCC tissues and higher Lnc-PLA2G4A-4 was remarkably related to tumor size, microvascular invasion and poor prognosis of HCC patients. Functionally, Lnc-PLA2G4A-4 positively regulated cell proliferation, invasion and migration in vitro, and facilitate lung metastasis of HCC in vivo. Mechanistically, Lnc-PLA2G4A-4 functioned as a competing endogenous RNA (ceRNA) to bind to miR-23b-3p and subsequently facilitated miR-23b-3p’s target gene versican (VCAN) expression in HCC cells. Over-expression of miR-23b-3p could reversed cell phenotypes caused by Lnc-PLA2G4A-4 in HCC and suppress the expression of versican by rescue analysis. Collectively, Lnc-PLA2G4A-4 promotes the progression of HCC via targeting miR-23b-3p/versican axis, which might be a potential biomarker and therapeutic target for HCC.

Moesin has been proved to be implicated in invasiveness and metastasis in many other cancers, but unclear in HCC. Thus, this study was performed to investigate the clinical significance of moesin and its biological functions in HCC. The results showed that moesin was significantly up-regulated in HCC tissues and was an independent prognostic factor for predicting the recurrence of HCC patients, postoperatively. Furthermore, we also demonstrated that moesin promoted the migration and invasion of HCC cells in vitro and in vivo. And the mechanism studies indicated that moesin overexpression increased the formation of invadopodia and improved the activation of β-catenin/MMP9 axis. Taken together, our findings revealed that moesin acted as an important onco-protein participating in the metastasis of HCC.

Background: The purpose of this study was to evaluate the safety and efficacy of endovascular brachytherapy (EVBT) combined with transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC) complicated with type III-IV portal vein tumor thrombosis (PVTT) and to further analyze the major independent risk predictor factors of prognosis.Methods: We retrospectively analyzed the medical records of 54 patients who were diagnosed with HCC complicated with type III or IV PVTT and who received EVBT combined with improved TACE treatment from January 2017 to June 2019. Adverse events, treatment response, overall survival (OS), progression-free survival (PFS), and stent patency were analyzed to evaluate the efficacy and safety of this treatment. Major independent risk predictors of OS were also analyzed by the regression model.Results: No severe adverse events associated with EVBT combined with TACE were observed. The objective response and disease control rates four weeks after the treatment were 42.6% and 96.3%, respectively. The median OS and PFS were 209±46.5 days and 138±29.4 days, respectively. The cumulative stent patency rate was 70.4% at the last follow-up. AFP≥400 ng/ml, ECOG PS>1, Child-Pugh grade B, and nonhemihepatic HCC were independent risk predictors of OS.Conclusions: EVBT combined with TACE was effective and safe for the treatment of HCC with type III-IV PVTT.

Poor prognosis of hepatocellular carcinoma (HCC) patients is frequently associated with rapid tumor growth, recurrence and drug resistance. MT1G is a low-molecular weight protein with high affinity for zinc ions. In the present study, we investigated the expression of MT1G, analyzed clinical significance of MT1G, and we observed the effects of MT1G overexpression on proliferation and apoptosis of HCC cell lines in vitro and in vivo. Our results revealed that MT1G was significantly downregulated in tumor tissues, and could inhibit the proliferation as well as enhance the apoptosis of HCC cells. The mechanism study suggested that MT1G increased the stability of p53 by inhibiting the expression of its ubiquitination factor, MDM2. Furthermore, MT1G also could enhance the transcriptional activity of p53 through direct interacting with p53 and providing appropriate zinc ions to p53. The modulation of MT1G on p53 resulted in upregulation of p21 and Bax, which leads cell cycle arrest and apoptosis, respectively. Our in vivo assay further confirmed that MT1G could suppress HCC tumor growth in nude mice. Overall, this is the first report on the interaction between MT1G and p53, and adequately uncover a new HCC suppressor which might have therapeutic values by diminishing the aggressiveness of HCC cells.

The programmed death (PD) pathway is frequently present in the tumor microenvironment (TME) and suppresses tumor immunity by inhibiting the activity of tumor-infiltrating lymphocytes (TILs), particularly, CD8+ lymphocytes. PD immunotherapy involves stimulation of the immune response in the region surrounding the tumor but is insufficient to prevent tumor progression. Therefore, in this study, we examined the effects of combined PD immunotherapy with fractionated radiotherapy (RT) on antitumor immunity and tumor growth in lymphoma. The immune cell profiles of the TME, blood, and secondary lymphoid organs were determined 7 days after treatment. Four combination therapies were compared. The synergistic effects of αPD-1 mAb and fractionated RT on increased CD8+ lymphocytes in the TME, blood, and secondary lymphoid organs led to substantial tumor regression in mouse EL4 lymphoma, both locally and systemically. Fractionated RT for 4 days followed by αPD-1 mAb therapy was significantly superior to other schemes in terms of overall survival rates and curative rates in xenograft model mice. Our data indicated that substantial immune responses occurred following combination therapy with fractionated RT and αPD-1 mAb immunotherapy. Our findings provide important insights into the use of RT plus αPD-1 mAb as an efficacious combinatorial therapy.