Cancer letters最新文献

DNA- and RNA-binding proteins (DRBPs) are versatile proteins capable of binding to both DNA and RNA molecules. In this study, we identified fibrillarin (FBL) as a key DRBP that is upregulated in liver cancer tissues vs. normal tissues and is correlated with patient prognosis. FBL promotes the proliferation of liver cancer cells both in vitro and in vivo. Mechanistically, FBL interacts with the transcription factor KHSRP, thereby regulating the expression of genes involved in glucose metabolism and leading to the reprogramming of glucose metabolism. Specifically, FBL and KHSRP work together to transcriptionally activate the glycolytic enzyme PFKFB4 by co-occupying enhancer and promoter elements, thereby further promoting liver cancer growth. Collectively, these findings provide compelling evidence highlighting the role of FBL as a transcriptional regulator in liver cancer cells, working in conjunction with KHSRP. The FBL/KHSRP-PFKFB4 regulatory axis holds potential as both a prognostic indicator and a therapeutic target for liver cancer.

Significance

A novel role of FBL in the transcriptional activation of PFKFB4, leading to glucose metabolism reprogramming in liver cancer.

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor characterized by extensive angiogenesis. However, the underlying mechanisms of HCC pathogenesis remain unclear. Previous studies have shown that RNA-binding proteins (RBPs) are implicated in HCC pathogenesis. In this study, we observed that increased RBM28 expression in HCC tissues was positively correlated with tumor microvascular density and negatively correlated with patient prognosis. Overexpression of RBM28 in HCC cells promoted tubule formation in human umbilical vein endothelial cells, whereas inhibition of RBM28 had the opposite effect, furthermore, the role of RBM28 in the progression of HCC was assessed using transgenic mouse models and chemically induced HCC models. We used various molecular assays and high-throughput detection methods to evaluate the role of RBM28 in promoting angiogenesis in HCC. Increased RBM28 expression in HCC directly binds to STAT3 mRNA, recruiting EIF4E to increase STAT3 expression and enhancing the secretion and expression of vascular endothelial growth factor A; consequently, promoting neovascularization in HCC. The potential of RBM28 as a viable diagnostic and therapeutic target for HCC was assessed using multi-cohort clinical samples and animal models. In summary, our results provide insights into the pathogenesis, clinical diagnosis, and treatment of HCC.

Abnormal metabolism has emerged as a prominent hallmark of cancer and plays a pivotal role in carcinogenesis and progression of lung adenocarcinoma (LUAD). In this study, single-cell sequencing revealed that the metabolic enzyme 6-phosphogluconate dehydrogenase (PGD), which is a critical regulator of the pentose phosphate pathway (PPP), is significantly upregulated in the malignant epithelial cell subpopulation during malignant progression. However, the precise functional significance of PGD in LUAD and its underlying mechanisms remain elusive. Through the integration of TCGA database analysis and LUAD tissue microarray data, it was found that PGD expression was significantly upregulated in LUAD and closely correlated with a poor prognosis in LUAD patients. Moreover, in vitro and in vivo analyses demonstrated that PGD knockout and inhibition of its activity mitigated the proliferation, migration, and invasion of LUAD cells. Mechanistically, immunoprecipitation-mass spectrometry (IP-MS) revealed for the first time that IQGAP1 is a robust novel interacting protein of PGD. PGD decreased p-AMPK levels by competitively interacting with the IQ domain of the known AMPKα binding partner IQGAP1, which promoted glycolysis and fatty acid synthesis in LUAD cells. Furthermore, we demonstrated that the combination of Physcion (a PGD-specific inhibitor) and metformin (an AMPK agonist) could inhibit tumor growth more effectively both in vivo and in vitro. Collectively, these findings suggest that PGD is a potential prognostic biomarker and therapeutic target for LUAD.

PARPi is currently the most important breakthrough in the treatment of ovarian cancer in decades, and it has been integrated into the initial maintenance therapy for ovarian cancer. However, the mechanism leading to PARPi resistance remains unelucidated. Our study aims to screen novel targets to better predict and reverse resistance to PARPi and explore the potential mechanism. Here, we conducted a comparative analysis of differentially expressed genes between platinum-sensitive and platinum-resistant groups within the TCGA ovarian cancer cohort. The analysis indicated that lncRNA PART1 was significantly highly expressed in platinum-sensitive patients compared to platinum-resistant individuals in TCGA-OV cohort and further validated in the GEO dataset and Qilu hospital cohort. Moreover, the upregulation of PART1 was positively correlated with a favorable prognosis in ovarian cancer. Furthermore, in vitro and in vivo experiments showed that inhibition of PART1 conferred resistance to both cisplatin and PARP inhibitor and promoted cellular senescence. Senescent cells are more resistant to chemotherapeutics. RNA antisense purification and RNA immunoprecipitation assays revealed an interaction between PART1 and PHB2, a crucial mitophagy receptor. Knockdown of PART1 could promote the degradation of PHB2, impairing mitophagy and leading to cellular senescence. Rescue assays indicated that overexpression of PHB2 remarkably diminished the resistance to PARPi and cellular senescence caused by PART1 knockdown. PDX models were utilized to further confirm the findings. Altogether, our study demonstrated that lncRNA PART1 has the potential to serve as a novel promising target to reverse resistance to PARPi and improve prognosis in ovarian cancer.

Acquired resistance to endocrine treatments remains a major clinical challenge. In this study, we found that desmoglein-2 (DSG2) plays a major role in acquired endocrine resistance and cellular plasticity in ER⁺ breast cancer (BC). By analysing the well-established fulvestrant-resistant ER⁺ BC model using single-cell RNA-seq, we revealed that ER inhibition leads to a specific increase in DSG2 in cancer cell populations, which in turn enhances desmosome formation in vitro and in vivo and cell phenotypic plasticity that promotes resistance to treatment. DSG2 depletion reduced tumorigenesis and metastasis in fulvestrant-resistant xenograft models and promoted fulvestrant efficiency. Mechanistically, DSG2 forms a desmosome complex with JUP and Vimentin and triggers Wnt/PCP signalling. We showed that elevated DSG2 levels, along with reduced ER levels and an activated Wnt/PCP pathway, predicted poor survival, suggesting that a DSG2^high signature could be exploited for therapeutic interventions. Our analysis highlighted the critical role of DSG2-mediated desmosomal junctions following antiestrogen treatment.

Histone lysine-specific demethylase 1 (LSD1) is frequently overexpressed in triple negative breast cancer (TNBC), which is associated with worse clinical outcome in TNBC patients. However, the underlying mechanisms by which LSD1 promotes TNBC progression remain to be identified. We recently established a genetically engineered murine model by crossing mammary gland conditional LSD1 knockout mice with Brca1-deficient mice to explore the role of LSD1 in TNBC pathogenesis. Cre-mediated Brca1 loss led to higher incidence of tumor formation in mouse mammary glands, which was hindered by concurrent depletion of LSD1, indicating a critical role of LSD1 in promoting Brca1-deficient tumors. We also demonstrated that the silencing of a tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), is functionally associated with LSD1-mediated TNBC progression. Mouse Brca1-deficient tumors exhibited elevated LSD1 expression and decreased TFPI2 level compared to normal mammary tissues. Analysis of TCGA database revealed that TFPI2 expression is significantly lower in aggressive ER-negative or basal-like BC. Restoration of TFPI2 through LSD1 inhibition increased H3K4me2 enrichment at the TFPI2 promoter, suppressed tumor progression, and enhanced antitumor efficacy of chemotherapeutic agent. Induction of TFPI2 by LSD1 ablation downregulates activity of matrix metalloproteinases (MMPs) that in turn increases the level of cytotoxic T lymphocyte attracting chemokines in tumor environment, leading to enhanced tumor infiltration of CD8⁺ T cells. Moreover, induction of TFPI2 potentiates antitumor effect of LSD1 inhibitor and immune checkpoint blockade in poorly immunogenic TNBC. Together, our study identifies previously unrecognized roles of TFPI2 in LSD1-mediated TNBC progression, therapeutic response, and immunogenic effects.

Desmoplasia in fibroblasts within metastatic lymph nodes (MLNs) serves as an indicator of extranodal extension (ENE), which led mortality in oral squamous cell carcinoma (OSCC). However, systematic studies on fibroblasts in MLNs are lacking. Therefore, this study characterized the differences in phenotype, function, and origin of fibroblasts between primary tumors (PTs) and lymph nodes (LNs) in OSCC.

We generated single-cell maps of PTs and paired MLNs and draining LNs from three OSCC patients. The transcriptomic atlas, pseudotime analysis, intercellular communication networks and enrichment analysis of the single cells were characterized. Phenotype and function heterogeneity of fibroblast cells between PTs and MLNs were further verified in vitro.

Among 44,052 fibroblasts, we identified two distinct subpopulations of cancer-associated myofibroblastic cells (mCAFs): RGS4⁺ mCAF1 and COMP ⁺ mCAF2. Notably, they exhibited distinct distributions, with mCAF1 predominantly localized in the PTs and mCAF2 in the MLNs. Moreover, pseudotime analysis revealed their distinct origins: mCAF1 originated from inherent normal myofibroblastic cells in the PT, whereas mCAF2 originated from fibroblastic reticular cells in the LNs. Further functional experiments using primary fibroblasts revealed that, compared to mCAF1, mCAF2 in MLNs exhibited weaker crosstalk with immune cells but enhanced extracellular matrix activity, which is closely linked to ENE formation in OSCC. Additionally, we identified two fibroblast subgroups in a transforming state, indicating a potential epithelial–mesenchymal transition.

Our research offers profound insights into the heterogeneity of fibroblasts between the PT and MLN in OSCC, serving as an essential resource for future drug discovery endeavors.

Metastatic clear cell renal cell carcinoma has heterogenous tumor microenvironment (TME). Among the metastatic lesions, pancreas metastasis is rare and controversy in treatment approaches. Here, extensive primary and metastatic lesion samples were included by single-cell RNA-seq to decipher the distinct metastasis TME. The hypoxic and inflammatory TME of pancreas metastasis was decoded in this study, and the activation of PAX8-myc signaling, and metabolic reprogramming were observed. The active components including endothelial cells, fibroblasts and T cells were profiled. Meanwhile, we also evaluated the effect of anti-angiogenesis treatment in the pancreas metastasis patient. The potential mechanisms of pancreatic tropism, instability of genome, and the response of immunotherapy were also discussed in this work. Taken together, our findings suggest a clue to the heterogeneity in metastasis TME and provide evidence for the treatment of pancreas metastasis in renal cell carcinoma patients.