Oncogenesis最新文献

Aberrant Receptor Tyrosine Kinase (RTK) signaling allows cancer cells to modulate survival, proliferation, and death, leading to tumorigenesis and chemoresistance. In leukemia, the RTK FMS-Related Tyrosine Kinase 4 (FLT4) (also known as VEGFR3, Vascular Endothelial Growth Factor Receptor- 3) is deregulated and correlates with cancer progression. However, the underlying consequences of its deregulation remain to be determined. Moreover, chemotherapy treatment requires that cancer cells retain a wild-type p53 to respond to DNA damage by tumor-suppressing activities, i.e. apoptosis. p53 activity is predominantly limited by its two major negative regulators, MDM2 and MDMX, which inactivate p53 by promoting its degradation and/or cytoplasmic localization. In this study, we have shown that activation of FLT4 by either overexpression or binding of its ligand, VEGFC, increases MDM2/MDMX stability, inactivates p53, and leads to resistance to DNA-damaging therapies. Moreover, we found that MDMX Ser-314 phosphorylation, a consensus sequence of CDK4/6, increases MDMX stability, which subsequently affects MDM2 and p53 degradation and could be reversed by the CDK4/6 inhibitor Palbociclib. More importantly, leukemic cells treated with Palbociclib were more susceptible to DNA-damaging induction of apoptosis and had reduced cell proliferation. Leukemic cells overexpressing FLT4 displayed accelerated proliferation when injected into NOD-SCID mice as compared to wild-type cells. Altogether, our research proposes an innovative way to reactivate p53 in leukemia through the pharmacological inhibition of FLT4 signaling, which could serve as a potential treatment option. Schematic representation of FLT4-mediated MDM2/MDMX complex stabilization and suppression of p53 activity. VEGFC triggers FLT4 activation, leading to CDK4/6 activation, which phosphorylates MDMX on Ser-314. As a result, MDMX levels increase and bind to MDM2, stabilizing the MDM2/MDMX complex. This complex binds to p53, facilitating its suppression by reducing its transcriptional activity or enhancing its export to the cytoplasm for proteasomal degradation. Consequently, p53 inactivation promotes their survival, proliferation, and resistance to chemotherapy-induced apoptosis. The figure was created in BioRender.com.

The oncoprotein MYCN drives malignancy in various cancer types, including neuroblastoma (NB). However, our understanding of the mechanisms underlying its transcriptional activity and oncogenic function, as well as effective strategies to target it, remains limited. We discovered that MYCN interacts with the transcriptional coactivator KAT2A, and this interaction significantly contributes to MYCN's activity in NB. Our genome-wide analyses indicate MYCN recruits KAT2A to bind to DNA, thereby transcriptionally regulating genes associated with ribosome biogenesis and RNA processing. Moreover, we identified that MYCN directly activates KAT2A transcription, while KAT2A acetylates MYCN, increasing MYCN protein stability. Consequently, MYCN and KAT2A establish a feedforward loop that effectively regulates global gene expression, governing the malignant NB phenotype. Treatment of NB cells with a KAT2A Proteolysis Targeting Chimera (PROTAC) degrader reduces MYCN protein levels, antagonizes MYCN-mediated gene transcription regulation and suppresses cell proliferation. This study highlights the potential of transcriptional cofactors as viable targets for developing anti-MYCN therapies.

Follicular thyroid carcinoma (FTC) is a common endocrine malignancy characterized by a higher propensity for invasion and metastasis compared to papillary thyroid carcinoma (PTC). Ephrin type A receptor 5 (EPHA5) is a crucial receptor tyrosine kinase involved in orchestrating diverse physiological processes, including apoptosis and proliferation. However, the mechanism of EPHA5 in FTC remains unclear. This study identified significant overexpression of EPHA5 in FTC. In vitro experiments showed that increased expression of EPHA5 promotes proliferation and inhibits apoptosis in FTC. Furthermore, EPHA5 activates the STAT3 signaling pathway. To explore the interaction between EPHA5 and the STAT3 signaling pathway, we used SH-4-54 (a STAT3-specific inhibitor). Interestingly, the influence of EPHA5 on proliferation and apoptosis was reduced upon combination with SH-4-54. In summary, this study unveils the involvement of the EPHA5-STAT3 signaling pathway in FTC and implies that the function of EPHA5 in FTC may partly depend on the STAT3 signaling pathway.

Fructose-1,6-bisphosphatase 1 (FBP1), a rate-limiting enzyme in gluconeogenesis, is important for cancer progression. The post-translational regulation of FBP1 in hypoxic environments is still unclear. Here, we report that FBP1 is down-regulated, and a low expression level of FBP1 predicts a poor prognosis in pancreatic cancer. A hypoxic environment makes FBP1 more prone to degradation, and this effect can be reversed by inhibiting global O-GlcNAcylation signalling. O-linked N-acetylglucosamine transferase (OGT) interacts with FBP1 and induces its O-GlcNAcylation at serine 47 residue (FBP1-S47) to modulate its protein function in pancreatic cancer cells. O-GlcNAcylation of FBP1-S47 promotes FBP1 degradation and also influences the expression of canonical HIF-1α target genes involved in glucose metabolism, resulting in an increase in glucose uptake and lactate secretion in pancreatic cancer cells. In addition, O-GlcNAcylation of FBP1-S47 facilitates FBP1 K48-linked polyubiquitination at lysine 51 residue (FBP1-K51), in which GlcNAc moiety can serve as a prerequisite for an FBP1 ubiquitin ligase. FBP1 (K51) K48-linked polyubiquitination mediated protein degradation can also promote cancer progression, similarly to the O-GlcNAcylation of FBP1-S47. Our data uncover a mechanism whereby FBP1 can be regulated by a protein O-GlcNAcylation-polyubiquitination axis, paving the way to cancer cell metabolic reprogramming.

MicroRNAs (miRNAs) are important regulators of gene expression whose dysregulation is widely linked to tumourigenesis, tumour progression and Epithelial-Mesenchymal Transition (EMT), a developmental process that promotes metastasis when inappropriately activated. However, controversy has emerged regarding how many functional miRNAs are encoded in the genome, and to what extent non-regulatory products of RNA degradation have been mis-identified as miRNAs. Central to miRNA function is their capacity to associate with an Argonaute (AGO) protein and form an RNA-Induced Silencing Complex (RISC), which mediates target mRNA suppression. We report that numerous "miRNAs" previously reported in EMT and cancer contexts, are not incorporated into RISC and are not capable of endogenously silencing target genes, despite the fact that hundreds of publications in the cancer field describe their roles. Apparent function can be driven through the expression of artificial miRNA mimics which is not necessarily reflective of any endogenous gene regulatory function. We present biochemical and bioinformatic criteria that can be used to distinguish functional miRNAs from mistakenly annotated RNA fragments.

Bone-marrow mesenchymal stem cells (BM-MSCs) rely on glycolysis, yet their trafficked mitochondria benefit recipient cells’ bioenergetics in regenerative and cancerous settings, most relevant to BM-resident multiple myeloma (MM) cells. Fission/fusion dynamics regulate mitochondria function. Proteomics demonstrates excessive mitochondrial processes in BM-MSCs from MM patients compared to normal donors (ND). Thus, we aimed to characterize BM-MSCs (ND, MM) mitochondrial fitness, bioenergetics and dynamics with a focus on therapeutics. MM-MSCs displayed compromised mitochondria evidenced by decreased mitochondrial membrane potential (ΔΨm) and elevated proton leak. This was accompanied by stimulation of stress-coping mechanisms: spare respiratory capacity (SRC), mitochondrial fusion and UPR^mt. Interfering with BM-MSCs mitochondrial dynamics equilibrium demonstrated their significance to bioenergetics and fitness according to the source. While ND-MSCs depended on fission, reducing MM-MSCs fusion attenuated glycolysis, OXPHOS and mtROS. Interestingly, optimization of mtROS levels is central to ΔΨm preservation in MM-MSCs only. MM-MSCs also demonstrated STAT3 activation, which regulates their OXPHOS and SRC. Targeting MM-MSC’ SRC with Venetoclax diminished their pro-MM support and sensitized co-cultured MM cells to Bortezomib. Overall, MM-MSCs distinct mitochondrial bioenergetics are integral to their robustness. Repurposing Venetoclax as anti-SRC treatment in combination with conventional anti-MM drugs presents a potential selective way to target MM-MSCs conferred drug resistance.

Glioblastoma (GBM) is one of the most malignant primary brain tumors, and factors governing its progression are not fully characterized. Recent research suggests that the long non-coding RNA (lncRNA) HOTAIR and super-enhancers (SEs) contribute significantly to GBM progression. Here, we performed TCGA data analysis revealing that high HOTAIR expression in GBM is associated with poor prognosis. Conversely, HOTAIR knock-down (KD) decreased proliferation, colony formation, and invasion of GBM cells. Furthermore, RNA-seq analysis identified DEGs in GBM cells related to cell growth and adhesion. Using an integrated approach, we also identify MEST as a HOTAIR-associated SE target gene. Intriguingly, MEST suppression in GBM cells phenocopied HOTAIR KD, as evidenced by reduced cell proliferation and invasion, whereas MEST overexpression counteracted effects of HOTAIR depletion. Moreover, 3 C technique-based PCR confirmed reduced interaction between HOTAIR-associated SEs and target genes after HOTAIR KD. This study reveals a novel regulatory mechanism governing GBM, offering promising directions for clinical interventions.

Up to 30% of acute myeloid leukemia (AML) patients face unfavorable outcomes due to the FMS-like receptor tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutation. Although FLT3 inhibitors show encouraging outcomes in treatment, they fail to eliminate leukemia stem cells, the origin of persistent and resistant lesions. Exploration of the mechanism in FLT3-ITD⁺ AML maintenance and chemoresistance is crucial for the development of novel therapeutic approaches. The manifestation of pluripotency transcription factors (TFs) and their link to clinical outcomes have been documented in various tumors. This study investigates the correlation between core pluripotency TF and treatment in AML. We discovered that FLT3 inhibition induced upregulation of OCT4 and NANOG in FLT3-ITD⁺ AML cells. Subsequently, we demonstrated that downregulation of OCT4 or NANOG inhibited cell growth, promoted apoptosis, and induced G0/G1 cell cycle phase arrest in FLT3-ITD⁺ AML cells. Knockdown of OCT and NANOG inhibited tumor growth in a mouse tumor model. OCT4 promotes the malignant biological behavior of FLT3-ITD⁺ AML by enhancing the abnormal FLT3 signaling pathway through transcriptional activation of NANOG. Importantly, downregulation of OCT4 or NANOG increased responsiveness to FLT3-tyrosine kinase inhibitor (TKI) (Gilteritinib), implying that OCT4 and NANOG may contribute to TKI resistance in FLT3-ITD⁺ AML. Our study verifies the involvement of OCT4/NANOG in regulating TKI sensitivity and targeting them may improve the cytotoxicity of FLT3-TKIs in FLT3-ITD⁺ AML.

Cancer-associated fibroblast (CAF) recruitment and activation within the tumor microenvironment (TME) are increasingly acknowledged as drivers of oral squamous cell carcinoma (OSCC) tumor growth and metastasis. Therefore, the mechanisms underlying tumor cell and fibroblast crosstalk warrant further investigation. We discovered that ectopic interferon-stimulated gene 15 (ISG15) expression, which is a promising and novel oncoprotein biomarker elevated in a variety of cancers, enhanced OSCC growth and elevated collagen and α-smooth muscle actin (α-SMA) expression in ISG15-expressing tumors. Analysis of immunohistochemistry revealed high ISG15 expression in human oral tissues correlated with high expression of α-SMA and fibroblast activation protein (FAP). Fibroblast migration and recruitment by ISG15-expressing OSCC cells were confirmed by in vitro and in vivo experiments. Exogenous ISG15 induced fibroblast migration, morphological changes, and vimentin expression. Enrichment of glycolysis pathway genes, as well as increased glycolysis-related gene expression, glucose uptake, and lactate production were observed in ISG15-treated fibroblasts. Lactate release and fibroblast migration were blocked by a competitive inhibitor of glucose metabolism. Furthermore, the knockdown of integrin αL (ITGAL)/CD11a, a subunit of ISG15 receptor lymphocyte functional-associated antigen-1 (LFA-1), in immortalized fibroblasts diminished extracellular ISG15-mediated glycolysis and migration. Our findings suggest that ISG15 derived from OSCC cells interacts with fibroblasts through the LFA-1 receptor, leading to glycolytic reprogramming and promotion of fibroblast migration into the TME.

The prevention and precise treatment of early-stage lung adenocarcinoma (LUAD) characterized by small nodules (stage IA) remains a significant challenge for clinicians, which is due largely to the limited understanding of the oncogenic mechanisms spanning from preneoplasia to invasive adenocarcinoma. Our study highlights the pivotal role of cancer cells exhibiting high expression of centromere protein F (CENPF), driven by TP53 mutations, which become increasingly prevalent during the transition from preneoplasia to invasive LUAD. Biologically, cancer cells (CENPF+) exhibited robust proliferative and stem-like capabilities, thereby propelling the malignant progression of early-stage LUAD. Clinically, autoantibodies against CENPF in the serum and elevated cancer cells (CENPF+) in tissue correlated positively with the progression of early-stage LUAD, especially those in stage IA. Our findings suggest that cancer cells (CENPF+) play a central role in orchestrating the malignant evolution of LUAD and hold potential as a novel biomarker for early-stage detection and management of the disease.