Research progress of the netrins and their receptors in cancer.

Netrins, a family of secreted and membrane-associated proteins, can regulate axonal guidance, morphogenesis, angiogenesis, cell migration, cell survival, and tumorigenesis. Four secreted netrins (netrin 1, 3, 4 and 5) and two glycosylphosphatidylinositols-anchored membrane proteins, netrin-G1 and G2, have been identified in mammals. Netrins and their receptors can serve as a biomarker and molecular therapeutic target for pathological differentiation, diagnosis and prognosis of malignant cancers. We review here the potential roles of the netrins family and their receptors in cancer.

A Case of Curative Treatment with Apatinib and Camrelizumab Following Liver Resection for Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), a highly malignant digestive system tumor, poses substantial challenges due to its intricate underlying causes and pronounced post-surgery recurrence. Consequently, the prognosis for HCC remains notably unfavorable. The endorsement of sorafenib and PD-L1 inhibitors for HCC signifies the onset of a new era embracing immunotherapy and targeted treatment approaches for this condition. Hence, comprehending the mechanisms underpinning targeted immune combination therapy has become exceedingly vital for the prospective management of HCC patients. This article initially presents a triumphant instance of curative treatment involving the combination of TKI and PD-1 inhibitor subsequent to liver resection, targeting an advanced stage HCC as classified by the BCLC staging system. The case patient carries a decade-long history of hepatitis B, having undergone a regimen of 20 courses of treatments involving apatinib and camrelizumab. Throughout the treatment period, no occurrences of grade 3 or 4 adverse events (AE) were noted. Subsequently, the patient underwent a left hepatectomy. Following the hepatectomy, their serum AFP levels have consistently remained within normal limits, and CT imaging has indicated the absence of tumor recurrence over a span of 36 months. The patient had been reviewed on time for two years after the operation. The last time a CT was performed for this patient in our hospital was 7 May 2021, and no new tumors were found. Follow-up is still ongoing. When applying combined targeted immune transformation therapy using TKI and ICI for a patient with BCLC advanced stage HCC, apatinib treatment serves a dual purpose. It inhibits the survival and angiogenesis of tumor cells, while also enhancing the efficacy of camrelizumab in obstructing the interaction between PD-1 and PD-L1. This restoration of T cell cytotoxicity subsequently facilitates the elimination of tumor cells, leading to an enhanced anticancer effect.

Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence.

Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type (Lgmn+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn-/-) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP's involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn+/+ primary neurons with the conditioned media derived from irradiated Lgmn+/+ or Lgmn-/- primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.

Integrating Single-Cell and Spatial Transcriptomics to Uncover and Elucidate GP73-Mediated Pro-Angiogenic Regulatory Networks in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) was characterized as being hypervascular. In the present study, we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed Golgi phosphoprotein 73 (GP73) HCC cells exerting cellular communication with vascular endothelial cells with high pro-angiogenesis potential via multiple receptor-ligand interactions in the process of tumor vascular development. Specifically, we uncovered an interactive GP73-mediated regulatory network coordinated with c-Myc, lactate, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, and endoplasmic reticulum stress (ERS) signals in HCC cells and elucidated its pro-angiogenic roles in vitro and in vivo. Mechanistically, we found that GP73, the pivotal hub gene, was activated by histone lactylation and c-Myc, which stimulated the phosphorylation of downstream STAT3 by directly binding STAT3 and simultaneously enhancing glucose-regulated protein 78 (GRP78)-induced ERS. STAT3 potentiates GP73-mediated pro-angiogenic functions. Clinically, serum GP73 levels were positively correlated with HCC response to anti-angiogenic regimens and were essential for a prognostic nomogram showing good predictive performance for determining 6-month and 1-year survival in patients with HCC treated with anti-angiogenic therapy. Taken together, the aforementioned data characterized the pro-angiogenic roles and mechanisms of a GP73-mediated network and proved that GP73 is a crucial tumor angiogenesis niche gene with favorable anti-angiogenic potential in the treatment of HCC.

RBM38 Reverses Sorafenib Resistance in Hepatocellular Carcinoma Cells by Combining and Promoting lncRNA-GAS5.

BACKGROUND: Hepatocellular carcinoma (HCC) is a life-threatening human malignancy and the fourth leading cause of cancer-related deaths worldwide. Patients with HCC are often diagnosed at an advanced stage with a poor prognosis. Sorafenib is a multikinase inhibitor used as the first-line treatment for patients with advanced HCC. However, acquired resistance to sorafenib in HCC leads to tumor aggression and limits the drug's survival benefits; the underlying molecular mechanisms for this resistance remain unclear. METHODS: This study aimed to examine the role of the tumor suppressor RBM38 in HCC, and its potential to reverse sorafenib resistance. In addition, the molecular mechanisms underlying the binding of RBM38 and the lncRNA GAS5 were examined. The potential involvement of RBM38 in sorafenib resistance was examined using both in vitro and in vivo models. Functional assays were performed to assess whether RBM38: binds to and promotes the stability of the lncRNA GAS5; reverses the resistance of HCC to sorafenib in vitro; and suppresses the tumorigenicity of sorafenib-resistant HCC cells in vivo. RESULTS: RBM38 expression was lower in HCC cells. The IC50 value of sorafenib was significantly lower in cells with RBM38 overexpression than in control cells. RBM38 overexpression improved sorafenib sensitivity in ectopic transplanted tumors and suppressed the growth rate of tumor cells. RBM38 could bind to and stabilize GAS5 in sorafenib-resistant HCC cells. In addition, functional assays revealed that RBM38 reversed sorafenib resistance both in vivo and in vitro in a GAS5-dependent manner. CONCLUSIONS: RBM38 is a novel therapeutic target that can reverse sorafenib resistance in HCC by combining and promoting the lncRNA GAS5.