Oncogene最新文献

Endocytosis is essential for cancer cell motility, which is predominantly mediated by the sorting nexin (SNX) family. Previous studies have demonstrated that SNX5 is elevated in several tumors, while its clinical significance and underlying mechanism in gastric cancer (GC) remain uninvestigated. In this study, we reported that SNX5 is highly expressed in GC and promotes the malignant biological behavior of GC cells. Its upregulation is closely related to poor prognosis in GC patients. Mechanistically, we observed an interaction between SNX5 and low-density lipoprotein receptor-related protein5 (LRP5) in GC cells. SNX5 inhibits LRP5 internalization and promotes its recycling to the cell membrane, which prevents LRP5 from being degraded in the lysosome. The increased membrane localization of LRP5 facilitates β-catenin stabilization, thus activating the Wnt signaling pathway, leading to tumorigenesis and progression.

Gastric cancer is one of the most common malignant tumors. Our previous study showed that PRSS23 expression is increased in human gastric cancer tissues and PRSS23 knockdown inhibits gastric cancer cell growth. This current study aims to uncover the mechanism underlying PRSS23's involvement in gastric tumorigenesis and progression. We established that PRSS23 influences gastric cancer growth both in vitro and in vivo by modulating the eIF4E-c-Myc axis (eIF4E, p-eIF4E, 4EBP1, p-4EBP1, and c-Myc). Our investigation revealed that PRSS23 interacts with eIF4E via its trypsin domain, while eIF4E binds to PRSS23 through the amino acid residue S209, as confirmed by co-IP and immunofluorescence assays. Multiplexed immunofluorescence assay demonstrated a significant elevation of PRSS23 and p-4EBP1 levels in 232 paired gastric cancer tissues. Moreover, in 49 patients exhibiting relatively high PRSS23 expression, the levels of eIF4E-c-Myc axis-related proteins were increased. Importantly, higher PRSS23 expression correlated significantly with increased lymph node metastasis and advanced clinical staging, leading to poorer patient prognosis. These results highlight the role of upregulated PRSS23 in promoting gastric tumorigenesis and progression by activating the eIF4E-c-Myc axis, underscoring the PRSS23-eIF4E-c-Myc axis as a promising therapeutic target for gastric cancer.

Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer. Unfortunately, this knowledge has not yet led to any breakthrough in cancer therapy. Thrombin is the key enzyme of blood coagulation system. The identification of a direct link between thrombin and the tumor progression remains unknown. We illustrated thrombin expression in lung adenocarcinoma (LUAD) was closely related to clinicopathological features, prognosis, and chemotherapy outcome of patients via TCGA and clinical pathological analysis. Using genetic and pharmacological approaches, we showed a direct link between thrombin catalytic activity and lung cancer progression in vitro and in vivo. Furthermore, we revealed that thrombin cleaves epidermal growth factor receptor (EGFR) at a GRG motif perfectly conserved across disparate species, indicating functional importance, which results in activation of EGFR/AKT/mTOR signaling pathway. Last we found the mutual interaction between thrombin and chemotherapy resistance. Combination therapy of thrombin inhibitor and chemotherapy results in improved anti-tumor efficacy. Together, our data firstly revealed a mechanism of cancer progression and chemotherapy resistance that involves thrombin-mediated EGFR cleavage. We propose that thrombin could be a prognostic biomarker for lung cancer, blockade of thrombin is a valuable therapeutic strategy to overcome cancer's resistance to chemotherapy.

N6-methyladenosine (m6A) plays a role in the development of tumors. However, the specific role of VIRMA, an RNA methyltransferase, in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study shows that VIRMA expression is elevated in PDAC. Increased VIRMA levels promoted PDAC growth and spread, while reducing VIRMA expression slowed these processes. VIRMA facilitated SLC43A2 mRNA degradation through an m6A-YTHDF2 pathway. The resulting decrease in SLC43A2 reduced phenylalanine absorption and oxidative stress, further driving PDAC progression. Furthermore, alcohol increased C/EBP β expression, which bound to VIRMA's promoter, enhancing its transcription. These findings suggest a connection between alcohol consumption, m6A modifications, and phenylalanine absorption in PDAC progression, offering a new approach to combat this disease.

RPA2, a key component of the RPA complex, is essential for single-stranded DNA (ssDNA) binding and DNA repair. However, the regulation of RPA2-ssDNA interaction and the recruitment of repair proteins following DNA damage remain incompletely understood. Our study uncovers a novel mechanism by which phosphorylated TRIM21 (Phospho-TRIM21) regulates RPA2 ubiquitination, thereby modulating homologous recombination and tumor radio/chemo-resistance. In the absence of DNA damage, TRIM21 mediates K63-linked ubiquitination of RPA2, countering K6-linked ubiquitination. Upon DNA damage, ubiquitination-modified RPA2 binds ssDNA, stabilizing the DNA structure and facilitating ATRIP/ATR recruitment. ATR subsequently phosphorylates TRIM21 at Ser41, leading to the dissociation of the TRIM21-RPA2 complex and a shift in RPA2 ubiquitination from K63 to K6 linkage. This shift maintains RPA2 ubiquitination homeostasis and stabilizes the RPA2-ATRIP complex, which is crucial for efficient homologous recombination (HR) repair and enhanced tumor radio/chemo-resistance. We also demonstrate that TRIM21 is frequently upregulated in cancers, and its depletion sensitizes cancer cells to radio/chemotherapy, suggesting its potential as a therapeutic target. This study provides novel insights into TRIM21's role in the DNA damage response and its implications for cancer treatment.