Molecular Cancer Research最新文献

Prostate tumor cells produce cholesterol de novo, and statin therapy targets the initial rate-limiting enzyme in this process, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). The extent to which the expression of HMGCR in prostate tumors could influence progression and predict the potential antineoplastic effects of statins remains unclear. In a prospective cohort study of 1,098 men diagnosed with primary prostate cancer from 1982 to 2009 in the Health Professionals Follow-up Study and Physicians' Health Study, 16% of prostate tumors showed strong HMGCR staining intensity, and 31% showed no staining. HMGCR expression was higher in tumors with PTEN loss but did not differ by statin use or long-term dietary cholesterol or saturated fat intake. Participants were followed for lethal events (distant metastases or prostate cancer-related death) over up to 32 years, and 96 lethal events occurred in those without metastases at diagnosis. Strong HMGCR expression was associated with higher rates of lethal prostate cancer (HR, 2.2; 95% confidence interval, 1.3-3.7), adjusting for age at diagnosis and Gleason score but without a linear dose response. In vitro, in the LNCaP human prostate cancer cell line, atorvastatin affected tumor cell viability in cells with experimentally lowered HMGCR expression. This study corroborates that high cholesterol synthesis in prostate tumor cells is associated with PTEN loss, aggressive tumor characteristics, and a greater risk of lethality.

Implications: High expression of HMGCR, the first rate-limiting enzyme of cholesterol synthesis, is a feature of prostate tumors that are more likely to progress to metastatic disease or death from prostate cancer.

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a pivotal enzyme in one-carbon metabolism, is significantly overexpressed in tongue squamous cell carcinoma (TSCC) and correlates with poor patient prognosis. Functional studies demonstrate that MTHFD2 drives TSCC proliferation and migration in vitro and in vivo, while its inhibition suppresses tumor progression. Mechanistically, MTHFD2 orchestrates a dual post-translational modification cascade: through its enzymatic activity, it simultaneously induces FOXO1 hypermethylation and ubiquitination, ultimately triggering ubiquitin-proteasome degradation of this tumor suppressor. This methylation-primed degradation axis is clinically validated by the inverse MTHFD2-high/FOXO1-low expression pattern in TSCC specimens, which predicts adverse outcomes. Critically, pharmacological inhibition of MTHFD2 (e.g., DS18561882) blocks FOXO1 degradation, establishing the MTHFD2-FOXO1 axis as a promising therapeutic target for TSCC through its novel metabolic-epigenetic regulatory mechanism. Implications: This study identifies the MTHFD2-FOXO1 axis as a druggable metabolic-epigenetic pathway in TSCC, providing both a prognostic marker and a therapeutic target.

Retinoblastoma (RB) is the most common pediatric eye cancer. Most cases of RB are initiated by bi-allelic mutational inactivation of the RB1 gene, yet most RB tumors harbor additional genomic aberrations that may promote tumor progression. After RB1, the gene that is most commonly mutated gene in RB is BCOR, which is mutated in approximately 20% of RB tumors and is associated with a more aggressive tumor phenotype and worse patient outcomes. Despite its importance, little is known about the role of BCOR in RB. Here, we interrogated BCOR in low passage RB cell lines using mass spectrometry, chromatin immunoprecipitation sequencing, and RNA sequencing. We show that the BCOR protein interacts with members of the ncPRC1.1 Polycomb Repressive Complex and localizes at gene loci with traditionally activating and repressing chromatin markers. Loss of BCOR downregulates the expression of genes associated with cell cycle regulation and upregulates genes associated with hypoxic adaptation. We conclude that BCOR mutations slow cell proliferation and drive hypoxic adaptation in RB via epigenetic mechanisms that may be amenable to targeted therapy. Implications: This study reveals that BCOR may play a noncanonical, multi-faceted role in retinoblastoma with implications in cell cycle, differentiation, and hypoxic adaptation, ultimately shedding insight into its molecular framework for future therapeutic strategies.

Colorectal cancer (CRC) 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 CRC pathogenesis. We analyzed 585 CRC samples and 329 normal samples from the Gene Expression Omnibus (GEO) database, creating a weighted gene co-expression network (WGCNA) across 24,069 genes. Through this approach, five modules associated with CRC were identified, which were enriched in MAPK signaling and cholesterol metabolism pathways. Using LASSO regression, we selected 13 hub genes (ABCB5, AOC1, ARHGAP44, CACNG3, 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 CRC patients. Machine learning validation confirmed the stability of these genetic markers. Experimental validation demonstrated increased levels of DBNDD1 and GDF15 in CRC, promoting constant NF-κB 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-IκB signaling. Additionally, DBNDD1 knockdown resulted in reduced tumor growth in vivo, highlighting that DBNDD1-GDF15-NF-κB signaling pathway drives CRC pathogenesis. Implications: This study highlights the crucial role of the DBNDD1/GDF15/NF-κB signaling pathway in CRC development, positioning DBNDD1 as a promising target for precision medicine strategies aimed at enhancing patient outcomes.

The pediatric and adolescent liver cancers, hepatoblastoma (HBL) and fibrolamellar hepatocellular carcinoma (FLC), respectively, are dangerous diseases requiring aggressive surgery, when feasible, and nontargeted toxic chemotherapy for a chance of cure due to insufficient knowledge of underlying molecular mechanisms. We have previously reported the essential role of ph-S675-β-catenin in the reorganization of genomic structure in HBL and FLC by oncogenic activation via chromosomal regions called cancer-enhancing genomic regions or aggressive liver cancer domains (CEGR/ALCD). In FLC, the fusion DNAJB1-PKAc (J-PKAc) oncoprotein phosphorylates β-catenin at Ser675, triggering such CEGRs/ALCDs-mediated activation of oncogenes. In this study, we found that all members of the cohesin ring-CTCF, Rad21, SMC1, SMC3, and STAG1-and β-catenin-TCF4 are bound to CEGRs/ALCDs of oncogenes in HBL and FLC, as well as many other cancers, and that this binding increases transcription. Examination of a large cohort of HBL and FLC samples revealed that cohesin ring expression is dramatically elevated in the majority. The cohesin ring, as well as the ph-S675-β-catenin-TCF4-p300 complex, is detected on both the promoter and intron-located CEGRs/ALCDs of NRF2 and Thy1, correlating with increased transcription. This suggests that the cohesin ring creates the DNA loop for oncogene activation. The inhibition of the cohesin ring by JQ1 reduces the proliferation of HBL and FLC cells in culture, as well as cells expressing the FLC-specific J-PKAc fusion oncogene.

Implications: These studies provide evidence that J-PKAc-β-catenin and the cohesin ring cooperate in oncogenic activation for both HBL and FLC.

Merkel cell carcinoma (MCC) is an aggressive disease with poor survival outcomes and increasing incidence. There is a clear and present need for enhanced understanding of cellular mechanisms of tumorigenesis, validation of robust genetic signatures predictive of aggressive disease, and novel informatics tools to simplify analysis of Merkel cell polyomavirus (MCPyV)-host genome interactions. Genomic DNA was harvested from 54 MCC tumors for exome sequencing and in-depth genetic profiling of a 226-gene panel. We further developed a robust informatics package (MCPyViewer) optimized for MCPyV integration site analysis with graphical output to simplify usability for end users. Finally, we assessed the prognostic impact of specific genetic signatures on MCC-specific survival in our cohort. Our study included 54 patients (n = 44 MCPyV positive), 11 (20.4%) of whom had died of MCC at last follow-up. Human genes altered at high frequency included LRP1B (n = 10, 18.5%), FAT1 (n = 9, 16.7%), KMT2D (n = 9, 16.7%), and RB1 (n = 7, 13.0%). In 36 of 44 (81.8%) MCPyV-positive tumors, we identified viral integration into the human genome with a median of two events per tumor. In six tumors, MCPyV integrated into Catalogue of Somatic Mutations in Cancer tier 1 or tier 2 cancer-related human genes.

Implications: A combined genomics score incorporating tumor mutational burden and copy-number variation was strongly prognostic of MCC-specific survival controlling for lymph node metastases and tumor MCPyV status; thus, our study adds critical understanding to prognostic markers and tumorigenic mechanisms in MCC.

Although transcriptomic studies have stratified pancreatic ductal adenocarcinoma (PDAC) into clinically relevant subtypes, classic or basal-like, further research is needed to identify the transcriptional regulators of each subtype. Previous studies identified HNF4α as a key regulator of the classic subtype. Still, the distinct contributions of its isoforms (P1 and P2), which display dichotomous functions in normal development and gastrointestinal malignancies, remain unexplored. In this study, we show that HNF4α-positive human PDAC tumors exhibit uniform expression of P2 isoforms but variable expression of P1 isoforms. To dissect the roles of each isoform in PDAC, we performed functional, transcriptomic, and epigenetic analyses after exogenous expression in HNF4α-negative models or CRISPRi-mediated knockdown of endogenous isoforms. We demonstrated that P1 isoforms are less compatible with growth and stronger transcriptional regulators than P2. Despite both isoforms sharing a common DNA-binding domain, P1 isoforms displayed stronger binding at HNF4α target genes, resulting in increased transcriptional activity. These findings provide a detailed characterization of HNF4α P1 and P2 isoforms and their distinct roles in PDAC biology.

Implications: HNF4α isoforms exhibit heterogeneous expression in PDAC and have distinct effects on proliferation and gene expression, including markers of clinically relevant molecular subtypes.

Intrahepatic cholangiocarcinoma (ICC) is the second most common liver cancer. LINC00519 plays a prominent role in the progression of numerous cancers. To explore the molecular mechanism of LINC00519 in ICC, the expressions of LINC00519, hsa-miR-22-3p, and MECOM in ICC were assessed using the ENCORI database and qRT-PCR. The biological functions of LINC00519 in ICC were examined using a clone formation experiment, Transwell analysis, flow cytometry, and Western blot. Meanwhile, the mechanism of LINC00519 in ICC was determined by a dual-luciferase reporter assay. Results showed that LINC00519 and MECOM were highly expressed in ICC, whereas hsa-miR-22-3p was decreased. Functionally, silencing LINC00519 weakened ICC cell proliferation and migration and induced cell apoptosis. Also, LINC00519 knockdown repressed the PI3K/AKT (protein kinase B) pathway. Mechanistically, LINC00519 acted as a competitive endogenous RNA to target MECOM by sponging hsa-miR-22-3p. Meanwhile, rescue assays further proved that low LINC00519 expression restrained ICC cell proliferation and migration and accelerated apoptosis through the PI3K/AKT pathway by miR-22-3p/MECOM. In conclusion, this research revealed a novel LINC00519/hsa-miR-22-3p/MECOM regulatory axis and PI3K/AKT pathway that modulated ICC progression.

Implications: This study deepens the understanding of the noncoding RNA regulatory network in ICC and provides potential targets for the diagnosis and targeted therapy of ICC.

Long noncoding RNAs act as modulators, with significant influence on a wide array of biological functions. They form an extensive communication network between genes and contribute to the pathophysiology of various human diseases, especially cancer. A growing body of research has demonstrated that long noncoding RNAs, acting either as promoters or inhibitors of oncogenesis, are intricately linked to the initiation and progression of cancer. Metastasis-associated colon cancer 1 antisense RNA1 (MACC1-AS1) is a newly identified long noncoding RNA that is abnormally expressed in various types of human tumors. Poor clinical characteristics, such as larger tumor size, advanced tumor stage, lymph node metastasis, and a lower overall survival rate, are linked to the overexpression of MACC1-AS1. MACC1-AS1 exerts a complex regulatory function: It acts as a competitive RNA, interacts with multiple proteins, and influences diverse pathways, leading to tumor development. It is essential to note the decreased efficacy of conventional chemotherapy drugs, which diminishes the efficacy of cancer treatment. Ongoing research has been highlighting the multifaceted functions of MACC1-AS1, and thus, it is required to unravel its exact molecular mechanisms. In this overarching review, we explore the significance of MACC1-AS1 as a potential cancer treatment target and biomarker. This study can potentially play an important role in the advancement of the field and confirm its potential clinical applicability.

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 to 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. Since CMA specifically targets proteins containing a pentapeptide motif (KFERQ-like motif) in a LAMP2A-dependent manner, we further employed an integrated proteomic-interactomic 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 knockdown of CMA receptor LAMP2A significantly increased SELENBP1 protein levels both in vitro and in vivo. CO-IP 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.