Background: NUAK1 is associated with metastasis and drug resistance in hepatocellular carcinoma (HCC). However, little is known about the immune functions of NUAK1 in HCC. Therefore, the aim of this study was to elucidate the novel role of NUAK1 in facilitating immune evasion in HCC and to investigate the mechanisms underpinning this process. Method: The levels of NUAK1 expression and the infiltration of CD8⁺ T cells were assessed in tumor tissues from HCC patients and mice xenograft model. HCC cell lines were used to validate the role of NUAK1 in regulating the transcription of PD-L1, the diethylnitrosamine-induced HCC model was established and the expression levels of NUAK1 and PD-L1 proteins in the rat livers were detected. Western blotting, immunofluorescence, real time PCR, and immunohistochemical staining were used to investigate the underlying mechanisms by which NUAK1 regulates PD-L1 expression in hepatocellular carcinoma. Results: NUAK1 expression was negatively correlated with CD8⁺ T cell infiltration in tumor tissues from HCC patients and mice xenograft model. Both gain and loss of functions have identified NUAK1 promoted PD-L1 expression at transcriptional level in HCC cells. The increased expression of NUAK1 and PD-L1 proteins were observed in the rat livers of diethylnitrosamine-induced HCC model. Moreover, overexpression of NUAK1 promotes GSK3β Ser⁹ phosphorylation, β-catenin expression and nuclear accumulation in HCC cells. By contrast, knockdown of NUAK1 has opposite effects. Inhibition of GSK3β activity significantly promoted β-catenin expression and PD-L1 expression in HCC cells. IHC analyses of tumor tissues from HCC patients suggested that the levels of p-GSK3β and β-catenin were positively correlated with NUAK1 expression. Knockdown of β-catenin also reversed NUAK1-mediated PD-L1 expression in HCC cells. Conclusions: This study revealed a novel role for NUAK1, which promotes the transcriptional expression of PD-L1 by activating GSK3β/β-catenin signaling pathway, leading to immune escape of hepatocellular carcinoma. Registry and the registration no. of the study/trial: Not applicable.

It is estimated that over 85% of human transcripts are non-coding RNAs, which play an important role in the regulation of numerous biological processes and are closely associated with the development of human cancers. Nevertheless, the functions of the vast majority of non-coding RNAs are yet to be clearly elucidated. Long non-coding RNA (lncRNA) LINC02320 was screened out by RNA-sequencing using paired CRC samples. The level of LINC02320 in colorectal cancer (CRC) tissues and cell lines was validated by qRT-PCR and in situ hybridization (ISH). CCK8, colony formation, transwell, wound healing and xenograft experiments were carried out to investigate the function of LINC02320. Antisense oligonucleotide (ASO) was used to target LINC02320. Mass spectrometry, pull-down, western blot and CUT&Tag assays were conducted to investigate the molecular mechanism of LINC02320, ILF2, GRB7, MAPK and FOS. LINC02320 was highly expressed in metastatic colorectal cancer (CRC) tissues based on RNA-sequencing. ISH staining using tissue microarray (TMA) indicated that LINC02320 is associated with the clinical stage and survival rate of patients with CRC. The results of loss-of-function and gain-of-function experiments demonstrated that LINC02320 facilitates cancer cell proliferation and metastasis in vitro and in vivo while simultaneously inhibiting apoptosis. LINC02320 is present in both the nucleus and cytoplasm, with a nuclear function. Mechanistically, LINC02320 recruits the transcriptional regulator ILF2 to the GRB7 promoter, thereby initiating its transcription. GRB7 then activates the mitogen-activated protein kinase (MAPK) signaling pathway, which contributes to CRC progression and leads to increased phosphorylation of the transcription factor FOS. Phosphorylated FOS directly promotes LINC02320 transcription, forming a positive feedback loop and amplifies this pro-cancer signal. Notably, LINC02320-targeted ASO therapy significantly blocked tumor growth in vivo. In summary, our findings demonstrate the essential role of LINC02320 involved in CRC progression, which provides novel insights into the importance of lncRNA as a therapeutic target in cancer treatment.

Colorectal cancer (CRC) is one of the most common causes of cancer-associated death worldwide, and a rapid increase in the incidence and mortality of CRC h

Introduction: Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), a highly pathogenic coronavirus (CoV) belonging to Coronavirus B, has triggered outbreaks or pandemics. Currently, many variants of SARS-CoV-2 have evolved, which exhibit severe immune evasion and imprinting resistance to existing vaccines and cause infected individuals to develop Post-Acute Sequelae of SARS-CoV-2 (also termed Long-COVID). This underscores the public health importance of developing effective vaccines with broad-spectrum efficacy against the SARS-CoV-2 variant and other CoVs with pandemic potential. Results: In this study, we expressed three tandem-repeat dimeric recombinant RBD proteins using an insect-baculovirus expression system integrated with the high-frequency SARS-CoV-2 RBD mutation sites. We performed immunogenicity assessment and attack protection tests. The date showed that these innovative SARS-CoV-2 RBD recombinant protein vaccines could show varying degrees of cross-immunity response and potent protection against SARS-CoV-2. Conclusion: Overall, our results indicated that these recombinant RBD subunit vaccines could serves a promising platform for a universal vaccine against SARS-CoV-2 and its variants, and provide a new perspective for the design of other future pandemic vaccines.

Background: Though apelin is involved in cardiovascular, metabolic, and homeostasis disorders, its role in alcohol-associated liver disease (ALD) remains unclear. This study aimed to investigate the mechanism of apelin in promoting hepatic inflammation in ALD. Methods: RAW 264.7 macrophages and a chronic alcohol-fed C57BL/6 mouse model were used. Apelin activated ERK1/2 phosphorylation, and PD98059 pretreatment attenuated apelin-induced MCP-1 and PCNA expression. Inflammatory and proliferative markers (MCP-1, IL-6, PCNA) were assessed by qRT-PCR and western blot. ERK signaling was evaluated using the inhibitor PD98059. Liver pathology was examined by H&E and Oil Red O staining. Results: Alcohol upregulated apelin expression in RAW 264.7 cells. Apelin-13 increased MCP-1 and PCNA expression in time- and dose-dependent manners. Apelin overexpression enhanced, while siRNA knockdown reduced, inflammatory and proliferative gene expression. Apelin activated ERK1/2 phosphorylation, and PD98059 pretreatment attenuated apelin-induced MCP-1 and PCNA expression. In vivo , apelin overexpression exacerbated steatosis, ballooning degeneration, and inflammatory infiltration, with elevated MCP-1, IL-6, and PCNA levels. Conclusion: Apelin aggravates inflammatory responses and hepatic steatosis in ALD via the ERK signaling pathway, suggesting that the apelin/APJ/p-ERK/inflammation axis may represent a novel therapeutic target for ALD.