Molecular Cancer Research最新文献

Ubiquitin-conjugating enzymes (E2s) are essential mediators of ubiquitin-dependent signaling cascades, governing diverse cellular processes such as proteolysis and transcriptional regulation. Despite increasing evidence linking E2 enzymes to tumorigenesis, their precise roles in gastric cancer (GC) remain incompletely defined. Here, we identified UBE2B as a key oncogenic E2 enzyme significantly upregulated in GC tissues through integrative bioinformatics analysis and clinical validation. High UBE2B expression was associated with poor patient prognosis and aggressive clinicopathological features. Functional assays demonstrated that UBE2B promotes GC cell proliferation both in vitro and in vivo. Mechanistically, UBE2B interacts with the E3 ligase BIRC2 to catalyze K63-linked ubiquitination of TRAF1, thereby amplifying NF-κB signaling. Furthermore, chromatin immunoprecipitation and luciferase reporter assays revealed that NF-κB subunit P65 directly binds to the UBE2B promoter, enhancing its transcription and forming a feedforward regulatory loop. This UBE2B-BIRC2-TRAF1 axis, coupled with the UBE2B-TRAF1-P65 feedback circuitry, establishes a self-sustaining mechanism that drives NF-κB hyperactivation and tumor cell proliferation. Collectively, our findings highlight UBE2B as a critical modulator of GC progression and a potential target for therapeutic intervention. Implications: This study characterizes the UBE2B-BIRC2-TRAF1 axis as a driver of NF-κB hyperactivation, identifying UBE2B as a prognostic biomarker and a potential therapeutic target for disrupting this oncogenic feedback loop in gastric cancer.

Colorectal cancer is a highly lethal gastrointestinal tract malignancy whose pathogenesis and molecular drivers are not fully understood. This study focused on searching for genes that are differentially expressed in cancer versus normal mucosa, with the goal of identifying molecular patterns of expression that are mechanistically linked to colorectal cancer pathogenesis. We analyzed 585 colorectal cancer samples and 329 normal samples from the Gene Expression Omnibus database, creating a weighted gene coexpression network analysis across 24,069 genes. Through this approach, five modules associated with colorectal cancer were identified, which were enriched in MAPK signaling and cholesterol metabolism pathways. Using least absolute shrinkage and selection operator (LASSO) regression, we selected 13 hub genes [ABCB5, AOC1, ARHGAP44, CACNG3, dysbindin domain-containing protein 1 (DBNDD1), GAS7, GTF2IRD1, PRSS22, SCN4A, TTC22, DLX6, PDK4, and SLC13A2] from these modules. Survival analysis indicated that higher expression of DBNDD1 correlated with worse overall survival in patients with colorectal cancer. Machine learning validation confirmed the stability of these genetic markers. Experimental validation demonstrated increased levels of DBNDD1 and growth differentiation factor 15 (GDF15) in colorectal cancer, promoting constant NF-κB (RELA) activation via DBNDD1-dependent GDF15 induction. Knocking down DBNDD1 inhibited cell proliferation, migration, and invasion in vitro (DLD1/HCT116 cells), alongside decreased GDF15 expression and reduced p-NF-κB p65-p-I-κB signaling. Additionally, DBNDD1 knockdown resulted in reduced tumor growth in vivo, highlighting that the DBNDD1-GDF15-NF-κB signaling pathway drives colorectal cancer pathogenesis.

Implications: This study highlights the crucial role of the DBNDD1-GDF15-NF-κB signaling pathway in colorectal cancer development, positioning DBNDD1 as a promising target for precision medicine strategies aimed at enhancing patient outcomes.

The most widely used cell line for studying ductal carcinoma in situ (DCIS) premalignancy is the transformed breast epithelial cell line, MCF10DCIS.com. During its original clonal isolation and selection, MCF10DCIS.com acquired a heterozygous M452I mutation in the proprotein convertase PCSK5, which has never been reported in any human cancer. The mutation is noteworthy because PCSK5 matures GDF11, a TGFβ superfamily ligand that suppresses progression of triple-negative breast cancer. We asked here whether PCSK5M452I and its activity toward GDF11 might contribute to the unique properties of MCF10DCIS.com. Using an optimized in-cell GDF11 maturation assay, we found that overexpressed PCSK5M452I was measurably active but at a fraction of the wild-type enzyme. In a PCSK5-/- clone of MCF10DCIS.com reconstituted with different PCSK5 alleles, PCSK5M452I was mildly defective in anterograde transport. However, the multicellular organization of PCSK5M452I addback cells in three-dimensional Matrigel cultures was significantly less circumscribed than wild-type and indistinguishable from a PCSK5T288P-null allele. Growth of intraductal MCF10DCIS.com xenografts was similarly impaired along with the frequency of comedo necrosis and stromal activation. In no setting did PCSK5M452I exhibit gain-of-function activity, leading us to conclude that it is hypomorphic and thus compensated by the remaining wild-type allele in MCF10DCIS.com.

Implications: This work reassures that an exotic PCSK5 mutation is not responsible for the salient characteristics of the MCF10DCIS.com cell line.

Castration-resistant prostate cancer, an advanced stage of prostate cancer, often leads to fatal bone metastasis. The vast majority of patients with prostate cancer who present with bone metastases suffer from bone lesions and other complications. Androgen receptor inhibitors, although improved, lack curative efficacy, necessitating an urgent demand for the development of innovative therapeutic strategies. TRIM28, also known as Krüppel-associated box-associated protein 1, is a transcription factor regulated by site-specific phosphorylation. Our recent study demonstrated that p90 ribosomal S6 kinase 1 is the protein kinase that directly phosphorylates TRIM28 at S473; as such, pS473-TRIM28 promotes the transcriptional activation of its gene targets. In this study, we reveal that TRIM28-S473 phosphorylation is readily detected in castration-resistant prostate cancer bone metastases, which is consistent with the previous report that p90 ribosomal S6 kinase is activated in prostate cancer bone metastases. Using bioinformatic and genomic analyses, we uncovered that lactate dehydrogenase A (LDHA) is a novel TRIM28-induced gene in bone metastatic prostate cancer. TRIM28 promotes the transcriptional activation of LDHA in a pS473-TRIM28-dependent manner. As such, TRIM28 is involved in LDH-related activities including lactate production and glycolysis. We also demonstrate that the TRIM28-LDHA axis is required for prostate tumor progression using an orthotopic bone injection model. Lastly, the application of an LDH inhibitor mitigates prostate cancer development in the bone. In summary, our study reveals an important role of the TRIM28-LDHA axis in prostate cancer progression in the bone, which may be targeted to mitigate the disease in the metastasis stage.

Implications: TRIM28 upregulates LDHA and glycolysis, propelling prostate tumors in the bone; pharmacologic LDH blockade mitigates disease.

Lysosome-associated membrane protein type 2A (LAMP2A) serves as the critical rate-limiting component of chaperone-mediated autophagy (CMA), governing substrate translocation into lysosomes. Accumulating studies indicate that LAMP2A downregulation leads to CMA impairment in multiple cancer malignancies. In this study, we found that LAMP2A is significantly upregulated in head and neck squamous cell carcinoma (HNSCC) compared with normal tissues. Cell functional studies performed on FaDu and CAL-27 cells showed that downregulation of LAMP2A inhibited cell proliferation and stemness and induced cell apoptosis. As CMA specifically targets proteins containing a pentapeptide motif (KFERQ-like motif) in a LAMP2A-dependent manner, we further employed an integrated proteomic-interactome approach combined with KFERQ motif analysis. This comprehensive strategy identified selenium-binding protein 1 (SELENBP1) as a novel putative CMA substrate in HNSCC. Subsequent validation confirmed that the knockdown of the CMA receptor LAMP2A significantly increased SELENBP1 protein levels both in vitro and in vivo. Coimmunoprecipitation assays confirmed that SELENBP1 interacts with the CMA chaperone protein heat shock cognate 71 kDa protein (HSPA8) in a KFERQ motif ("EKVIQ")-dependent manner. Overexpression of SELENBP1 attenuated HNSCC cell proliferation and viability. Most importantly, silencing of SELENBP1 partially rescued the tumor-suppressive phenotypes induced by LAMP2A knockdown, suggesting that SELENBP1 mediated the effects of LAMP2A knockdown on HNSCC. This study provides insights into the role of the LAMP2A-CMA-SELENBP1 axis in the development of novel therapies for HNSCC.

Implications: This study provides a novel insight into the role of CMA during the pathogenesis of HNSCC.

Lung cancer is a highly malignant tumor and prone to recurrence and metastasis. Adenocarcinoma is the most common subtype. LIM zinc finger domain containing 2 (LIMS2) was reported to inhibit growth and metastasis of several tumors, while its role in lung adenocarcinoma remains unclear. This study aims to expound the function of LIMS2 in lung adenocarcinoma. The analysis from medical databanks showed that LIMS2 was lowly expressed in lung adenocarcinoma specimens, compared with the normal lung tissues, and our clinical data demonstrated that LIMS2 expression was associated with TNM stage of lung adenocarcinoma patients. Gain- and loss-of-function experiments revealed that LIMS2 suppressed proliferation, invasion, migration, epithelial-mesenchymal transition of lung adenocarcinoma cells, delayed xenograft and orthotopic growth, and blocked distant metastasis and lymph infiltration in nude mice. The medium supernatant from LIMS2-overexpressed lung adenocarcinoma cells intercepted the activation of fibroblasts from lung cancer. The co-IP results demonstrated that an E3 ubiquitin ligase ring finger and CHY zinc finger domain containing 1 (RCHY1) interacted with LIMS2, and mediated its K48 ubiquitination and degradation. LIMS2 overexpression reversed the promoting effects of RCHY1 on proliferation, migration and lung cancer-fibroblast activation of lung adenocarcinoma cells. In conclusion, decreased LIMS2 may mediate the tumor-promoting role of RCHY1 in lung adenocarcinoma cells. Implications: These findings may provide novel diagnostic markers and therapeutic targets for lung adenocarcinoma in clinic.

One of the primary factors contributing to the failure of radiation therapy is the resistance of cancer cells to radiation. The identification of targets of radiation sensitization and exploration of the molecular mechanism of radioresistance are urgently needed. In this study, we demonstrate that the multifunctional chaperone protein C1QBP (component 1Q subcomponent-binding protein) is required for radioresistance and proliferation in lung cancer cells and tissues, C1QBP is significantly overexpressed, indicating poor prognosis. Blocking C1QBP in vivo and in vitro significantly reduces lung cancer proliferation and growth, increasing lung cancer radiosensitivity. In terms of mechanism, we observed that C1QBP interacts with STAT1 and promotes c-Myc-CHK1/CHK2 signaling axis activation. However, STAT1 is necessary for the influence of C1QBP on lung cancer proliferation and radiosensitivity. Implications: These findings establish C1QBP as a key regulator of lung cancer progression and radioresistance, revealing a novel therapeutic avenue for this disease.

The response to androgen-targeted therapy in prostate cancer (PCa) is highly heterogeneous. While previous studies have primarily concentrated on tumor cell-intrinsic signaling changes, the tumor microenvironment, particularly the interactions between tumor-infiltrating lymphocytes (TILs) and tumor cells, is equally critical in shaping treatment responses. Building on our previous observations linking TILs to treatment efficacy in the context of neoadjuvant androgen deprivation therapy (NADT), we employed publicly available clinical datasets, in vitro T cell-PCa cell co-culture systems, and murine xenograft models to investigate this interplay. We found treatment-related dynamic change in TILs populations, accompanied by a concordant expression pattern of FOSL2 and PD-L1. Mechanistically, FOSL2 directly bound to the PD-L1 promoter to transcriptionally upregulate PD-L1, thereby modulating T cell infiltration and function. Importantly, in vivo results demonstrated that targeting FOSL2 enhanced the antitumor effect when it combined with hormone therapy and anti-PD-L1 treatment. These findings suggest that FOSL2 may contribute to treatment response heterogeneity by shaping the tumor immune microenvironment, offering novel insights into resistance mechanisms and uncovering potential strategies to enhance the efficacy of hormone therapy in PCa. Implications: Targeting FOSL2-mediated PD-L1 regulation offers a promising strategy to overcome immune microenvironment-mediated resistance and improve the therapeutic efficacy of androgen-targeted therapy in PCa.

Data regarding the clinical outcomes of immune checkpoint inhibitor (ICI) therapy and tumor immune microenvironment (TIME) profiles in non-clear-cell renal cell carcinoma (nccRCC) remain limited. Herein, we retrospectively compared the effectiveness profile of first-line ICI combination therapy between clear-cell RCC (ccRCC) and nccRCC. Additionally, genome-wide gene expression and tumor-infiltrating immune cell (TIIC) profiling were performed using RNA-seq and flow cytometry, respectively. Of 266 patients, 56 (21%) were histopathologically diagnosed with nccRCC. Progression-free survival (PFS) (hazard ratio [HR], 0.59, p = 0.0059) and overall survival (OS) (HR, 0.42, p = 0.0006) were shorter in nccRCC patients than in ccRCC patients. Gene expression analysis of 140 RCC samples revealed the downregulation of immune-related and angiogenesis-related pathways in nccRCC. The survival difference between ccRCC and nccRCC was more significant with the combination of ICIs and VEGFR-TKIs (PFS: HR 0.45, p = 0.0026; OS: HR 0.26, p <0.0001) than with dual ICI combinations (PFS: HR 0.64, p = 0.0761; OS: HR 0.59, p = 0.131). TIIC profiling of 116 samples showed that nccRCC exhibited an "immune-cold" TIME phenotype characterized by a decrease in TIICs, including CD8+ T cells. In conclusion, the downregulation of immune-related pathways, caused by an "immune-cold" TIME phenotype, is potentially involved in the pathogenesis underlying the decrease in the therapeutic efficacy of ICI combination therapy for nccRCC. Implications: nccRCC harbors an "immune-cold" TIME phenotype characterized by reduced TIICs, which in turn drive the downregulation of immune-related pathways and may contribute to decreased responsiveness to ICI therapy.