The Wnt/β-catenin signaling pathway in the tumor microenvironment of hepatocellular carcinoma

The Wnt/β-catenin signaling pathway regulates many aspects of tumor biology,and many studies have focused on the role of this signaling pathway in tumor cells.However,it is now clear that tumor development and metastasis depend on the two-way interaction between cancer cells and their environment,thereby forming a tumor microenvironment(TME).In this review,we discuss how Wnt/β-catenin signaling regulates cross-interactions among different components of the TME,including immune cells,stem cells,tumor vasculature,and noncellular components of the TME in hepatocellular carcinoma.We also investigate their preclinical and clinical insights for primary liver cancer intervention,and explore the significance of using Wnt/β-catenin mutations as a biomarker to predict resistance in immunotherapy.

Cloning and expression of MXR7 gene in human HCC tissue

AIM To clone and identify the whole cDNA ofMXR7 gene and to find out its expression inhuman HCC,and normal tissues.METHODS The DNA primers were designed andsynthesized according to the whole cDNAsequence of MXR? gene.The cDNA of humanHCC was taken as the template while the cDNA ofMXR7 gene was synthesized by polymerasechain reaction（PCR）.Recombinant DNAconforming to reading frame was constructed byconnecting purified PCR product of the cDNA ofMXR? gene with expression vector pGEX-5X-1 offusion protein.The plasmid MXRT/pGEX-5X-1was identified by sequencing.Using 32p labeledMXR? cDNA as probe,MXR7 mRNA expressionwas detected by Northern blot analysis in 12different human normal tissues,7 preoperativelyuntreated non-liver tumor tissues,30preoperatively untreated HCC,theparacancerous liver tissues and 12 normal livertissues samples.RESULTS Restriction enzyme and sequenceanalysis confirmed that the insertion sequence invector pGEX-5X-1 was the same as the cDNAsequence of MXR7 gene.Northern blot analysisshowed no expression of MXR? mRNA in 12 kindsof normal human tissues including liver,7 tumortissues in other sites and 12 normal livertissues,the frequencies of MXR7 mRNA expression in HCC and paracancerous livertissues were 76.6% and 13.3%,respectively.The frequency of MXR7 mRNA expression in HCCwithout elevation of serum AFP and in HCC【5cm was 90%（9/10）and 83.3%（5/6）,respectively.CONCLUSION MXR7 mRNA is highly expressedin human HCC,which is specific and occurs at anearly stage of HCC,suggesting MXR7 mRNA canbe a tumor biomarker for HCC.The detection ofMXR7 mRNA expression in the biopsied livertissue is helpful in discovering early subclinicalliver cancer in those with negative serum AFP.

The Mechanism and Influence of AKAP12 in Different Cancers

The development of cancer is a complex process that requires the participation of many factors,including mutations in genes, regulation of signaling pathways, disruption of homeostasis, and failure of self-monitoring mechanisms. Sufficient evidence has

肝胆肿瘤中肿瘤特异性CircRNA衍生抗原肽的鉴定

基于肿瘤抗原的免疫治疗的应用受到验证免疫原性肽稀缺性的阻碍。本研究旨在研究环状RNA(circRNA)在肝胆肿瘤类器官中作为肿瘤抗原肽新来源的潜力。使用RNA测序(RNA-seq)和基于算法的评分工具,预测3950个翻译的肿瘤特异性环状RNA在27个类器官中产生18971个抗原肽。从抗原格局来看,11个氨基酸长度(mer)肽和人白细胞抗原(HLA)-A结合肽具有最高的免疫原性相关评分。在分析的3/5类器官中,有13个预测抗原肽通过质谱(MS)免疫肽组学被直接确认为HLA-A、HLA-B和HLA-C(HLA-ABC)结合肽。在流式细胞术和酶联免疫吸附试验(ELISA)中,由HLA-ABC分子呈递的circRNA衍生的肿瘤特异性肽刺激CD8(CD8)T细胞,显示CD107a干扰素γ(IFNγ)共表达和IFNγ分泌增加。免疫原性环状RNA衍生肽诱导的靶向类器官的细胞毒性T细胞活性在杀伤实验中得到验证。值得注意的是,来自circTBC1D15的抗原肽YGFNEILKK不仅被认为是类器官的HLA-ABC呈递肽,而且还显著降低了肿瘤类器官的存活率。本研究的发现强调了产生肿瘤抗原的一个关键亚群,这对靶向肿瘤特异性circRNA具有重要意义。

A Noninvasive Approach to Evaluate Tumor Immune Microenvironment and Predict Outcomes in Hepatocellular Carcinoma

It is widely recognized that tumor immune microenvironment(TIME)plays a crucial role in tumor progression,metastasis,and therapeutic response.Despite several noninvasive strategies have emerged for cancer diagnosis and prognosis,there are still lack of efective radiomic-based model to evaluate TIME status,let alone predict clinical outcome and immune checkpoint inhibitor(ICIs)response for hepatocellular carcinoma(HCC).In this study,we developed a radiomic model to evaluate TIME status within the tumor and predict prognosis and immunotherapy response.A total of 301 patients who underwent magnetic resonance imaging(MRI)examinations were enrolled in our study.The intra-tumoral expression of 17 immune-related molecules were evaluated using co-detection by indexing(CODEX)technology,and we construct Immunoscore(IS)with the least absolute shrinkage and selection operator(LASSO)algorithm and Cox regression method to evaluate TIME.Of 6115 features extracted from MRI,fve core features were fltered out,and the Radiomic Immunoscore(RIS)showed high accuracy in predicting TIME status in testing cohort(area under the curve=0.753).More importantly,RIS model showed the capability of predicting therapeutic response to anti-programmed cell death 1(PD-1)immunotherapy in an independent cohort with advanced HCC patients(area under the curve=0.731).In comparison with previously radiomicbased models,our integrated RIS model exhibits not only higher accuracy in predicting prognosis but also the potential guiding signifcance to HCC immunotherapy.

A mitochondria-targeted AIE photosensitizer for enhancing specificity and efficacy of ferroptosis inducer

Ferroptosis is a form of regulated cell death characterized by iron-dependent accumulation of lipid peroxidation and lethal reactive oxygen species(ROS).To date,misregulated ferroptosis has been implicated in several types of cancers,and ferroptosis inducers can be used to promote ferroptosis in tumor cells and play an anti-tumor role.However,the specificity and efficacy of ferroptosis inducers remain unsatisfactory.Here,a new mitochondria-targeted photosensitizer(PS)with aggregation-induced emission(AIE)characteristic named TCSVP was designed,which efficiently generates ROS in mitochondria after light exposure.TCSVP administration significantly sensitizes tumor cells to ferroptosis inducer(RSL3)-mediated cell death by specifically and light-dependently triggering a moderate ROS generation in vitro and in vivo.Mechanically,the expression levels of ferroptosis related proteins Acyl-CoA synthetase long-chain family member 4(FACL4/ACSL4)and cyclooxygenase-2(COX2)were increased in TCSVP/RSL3-treated cells after light exposure,coupled with decreased Glutathione peroxidase 4(GPX4)activity and excessive malondialdehyde(MDA)accumulation.This study declared that light-induced moderate ROS generation within mitochondria in cancer cells by AIE-PS can be used to enhance the specificity and efficacy of ferroptosis inducers,bringing a new synergistic strategy for tumor intervention.