Molecular Carcinogenesis最新文献

Heat shock cognate protein 70 (HSC70) functions as a molecular chaperone and plays a crucial role in the regulation of intracellular protein modifications that are involved in tumor autophagy. However, its expression and mechanism in breast cancer have not been studied. The expression of HSC70 was verified by TCGA database and breast cancer patient tissue. We established breast cancer cell models and mouse models using knockdown HSC70. The expression and mechanism of HSC70 in breast cancer were investigated by immunocoprecipitation, protein stability, RNA stability, flow cytometry and biogenic analysis. In this study, we found that HSC70 is highly expressed in breast cancer and that high HSC70 expression positive correlated with poor prognosis using TCGA database and patient tissue verification. Subsequent experimental verification demonstrated that HSC70 drives cell cycle progression and promotes proliferation in breast cancer. Further studies revealed that HSC70 significantly promoted the phosphorylation of PI3K, AKT and mTOR but did not affect the total protein levels. Additionally, the AKT agonist SC79 reversed the effects of HSC70 knockdown on proliferation and cell cycle progression of breast cancer cells. Mechanistically, HSC70 reduces the protein stability of PTEN but does not change its mRNA level, suggesting that HSC70 binds to PTEN and promotes its autophagic degradation. More importantly, in vivo experiments demonstrated that HSC70 knockdown results in slower tumor proliferation and growth. In conclusion, HSC70 can bind to PTEN and promote its autophagic degradation, thereby activating the PI3K/AKT/mTOR signaling pathway to promote cell cycle progression and proliferation in breast cancer. These findings suggest that HSC70 may be a feasible target for breast cancer treatment.

Lung cancer poses a serious threat to public health due to its high morbidity and mortality rates. The mechanisms of lung cancer formation and progression are complex and involve regulation of various biomolecules. Long noncoding RNAs (lncRNAs) have emerged to be critical in tumorigenesis of various malignancies. In this study, we identified candidate lncRNAs associated with occurrence and development of lung cancer by analyzing the differentially expressed lncRNAs in lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) cancer tissues and adjacent noncancerous tissues from UALCAN database. We found that LINC02562, which is highly expressed in LUAD and LUSC, can affect the occurrence and development of lung cancer in vivo and in vitro. Furthermore, LINC02562 competes with YBX1 to bind to the DNA repair protein NTHL1, which makes both the interaction between YBX1 and NTHL1, and the activity of NTHL1 in a balanced state, thereby promoting the progression of lung cancer. Additionally, the LINC02562/NTHL1/YBX1 axis represents a novel therapeutic target for lung cancer.

Epithelial-mesenchymal transition (EMT) and anoikis resistance are crucial characteristics for tumor cell metastasis. High-temperature requirement A1 (HTRA1) has been identified as a serine protease with chaperone functions, but its role in the regulation of EMT, anoikis resistance, and metastasis in colorectal cancer (CRC) remains poorly understood. In this study, we identified that HTRA1 was downregulated in CRC tissues, and its low expression was significantly associated with advanced TNM stage and poor prognosis. Loss of HTRA1 facilitated EMT and anoikis resistance in CRC cells, thereby potentiating metastatic potential both in vitro and in vivo. Conversely, HTRA1 overexpression produced opposite effects. Furthermore, we carried out RNA-seq and found that HTRA1 was probably involved in the regulation of Hippo/YAP1 pathway. HTRA1 overexpression led to increased phosphorylation of YAP1 and decreased nuclear translocation, which could be largely reversed by XMU-MP-1, an inhibitor of the Hippo pathway. Mechanistically, HTRA1 directly bound to and stabilized large tumor suppressor gene 2 (LATS2), a key kinase of the Hippo pathway, which contributed to the inactivation of YAP1. Restoring LATS2 expression in HTRA1-deficient CRC cells decreased EMT and anoikis resistance. Altogether, our findings unveiled the negative regulatory function of HTRA1 in CRC progression through the regulation of the Hippo/YAP1 pathway, and supported HTRA1 as a potential therapeutic target in CRC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy; however, no validated treatments are currently available. Clinically, the tumor position, head and uncinate process (HU), or body and tail (BT) of the pancreas are vital for surgical strategies; however, fundamental research has seldom revealed the heterogeneous tumor microenvironment (TME) among different types of PDAC. Here, we applied multicohort single-cell and spatial RNA-seq methods together with patient-derived organoid models to reveal the TME heterogeneity between HU and BT PDAC. Osteopontin, encoded by SPP1, is secreted by vessel endothelial cells in BT PDAC and is associated with increased tumor burden. The number of tumor cells marked by CRABP2 was lower in BT PDAC and was identified as a prognostic marker of overall survival, as well as CD8⁺ T-cell infiltration. The expression of CRABP2 was also validated to be downregulated in BT PDAC in patient-derived organoid models. Overall, we profiled the heterogeneous PDAC TME between HU and BT PDAC, which could provide novel insight into the relationships between clinical characteristics and TME molecular research.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy worldwide with a low survival rate due to a lack of therapeutic targets. Here we found that the mitochondria-related gene GrpE-like 2 (GRPEL2) transcript levels are significantly upregulated in ESCC patient samples, and its high expression predicts poor prognosis. Knockdown of GRPEL2 aggravated suppressed cell proliferation and colony formation. Conversely, overexpression of GRPEL2 promotes ESCC cell proliferation both In Vitro and In Vivo. We delved deeper into the effects of GRPEL2 on mitochondrial function and found that the depletion of GRPEL2 induced mitochondrial dysfunction and cellular apoptosis. Mechanistically, our RNA-Seq analysis revealed that suppression of GRPEL2 expression triggers activation of the MAPK/JNK signaling pathway. Additionally, the apoptosis induced by GRPEL2 loss can be largely reversed by treatment with SP600125, a JNK inhibitor. To further enhance the feasibility of targeting GRPEL2 for inhibiting ESCC proliferation in practical applications, we conducted computer-based drug screening to identify potential GRPEL2 inhibitors. We identified Vandetanib, a known antitumor agent, as a promising molecule that not only exhibits robust binding activity but also effectively reduces GRPEL2 protein levels. In conclusion, the data presented herein implicate GRPEL2 as a pivotal regulator in ESCC, modulating the MAPK/JNK signaling cascade to potentiate apoptosis, thereby offering a specific therapeutic vulnerability for targeting ESCC.

The current study aims to delineate the role of a novel anaplastic lymphoma kinase (ALK) transcript, ALK^ATI, in ovarian high-grade serous carcinoma (HGSC). Overexpressed ALK^ATI exhibited both cytoplasmic and nuclear localization in HGSC cells, whereas full-length ALK was predominantly cytoplasmic. ALK^ATI interacts with the DNA repair protein, poly (ADP ribose) polymer 1 (PARP1), and cells stably overexpressing ALK^ATI (OE- ALK^ATI) were more sensitive to cisplatin-induced apoptosis. Consistent with this, cleaved PARP1 levels were higher in HGSC tissue samples in areas with nuclear ALK immunoreactivity. The ratio of antiapoptotic BCL2 relative to proapoptotic BAX was significantly increased in OE-ALK^ATI cells, despite the increase in apoptosis, suggesting that ALK^ATI-mediated apoptosis is independent of mitochondrion-driven cell death. OE-ALK^ATI decreased epithelial-mesenchymal transition/cancer stem cell properties but did not alter proliferation rates, and nuclear ALK immunopositivity was not associated with clinicopathological factors or prognosis in HGSC. Together, our observations suggest that ALK^ATI sensitizes HGSC cells to apoptosis (probably though an association with PARP1) but this may have a relatively minor impact on tumor progression.

HPV16 CpG methylation is associated with cervical carcinogenesis and the expression of HPV16 tumorigenesis-related genes. However, the genome-wide methylation profile of HPV16 CpG sites during cervical carcinogenesis has not been fully characterized, and the regulatory role of HPV16 CpG methylation in the expression of these genes in cervical carcinogenesis remains unclear. This study aims to comprehensively map HPV16 CpG methylation patterns across different cervical carcinogenesis stages and elucidate its regulatory effect on the expression of HPV16 tumorigenesis-related genes as well as biological alterations in cervical cancer cells. A total of 341 participants diagnosed with various stages of cervical lesions and normal cervix were enrolled to evaluate the associations between HPV16 CpG methylation, expression of HPV16 tumorigenesis-related genes, and cervical carcinogenesis. Demethylation of HPV16 CpG sites in Caski cells using 5-Aza-dC was performed to assess subsequent changes in the expression of HPV16 tumorigenesis-related genes and cellular biological functions. HPV16 hypermethylation was associated with an increased risk of cervical cancer and precancerous lesions. Thirty-six specific CpG sites across various regions of the HPV16 genome exhibited progressively elevated methylation levels correlating with lesion severity. Effects of HPV16 CpGs methylation on cervical carcinogenesis were partially mediated by HPV16 oncoproteins. Demethylation of HPV16 CpGs significantly suppressed HPV16 oncogene expression, promoted apoptosis, and inhibited proliferation, migration, and invasion in cervical cancer cells. This study provides novel insights into the role of HPV16 CpG methylation in cervical carcinogenesis through the modulation of HPV16 oncogenes. This might represent a promising therapeutic strategy for impeding cervical cancer progression.

Studies from our lab demonstrated that increasing miR-200 expression in human triple negative breast cancer (TNBC) reduced tumor growth and metastasis In Vivo. In this study, we found that overexpression of miR-200s in TNBC cells significantly reduced the expression of JAG1. When JAG1 was knocked out in MDA-MB-231 cells proliferation and invasion were significantly reduced In Vitro. Moreover, loss of JAG1 inhibited mammary tumor growth and metastasis In Vivo. RNA sequencing revealed that loss of JAG1 altered the expression of genes associated with the ECM, angiogenesis, and EMT. These results imply that miR-200s may mediate some of their antitumor actions through reducing JAG1 expression and suggest that agents targeting JAG1 should be further evaluated as a therapeutic strategy for TNBC.

Recent research has increasingly suggested an association between changes in specific blood metabolites and prostate cancer (PCa) development. However, it remains unclear whether these observed associations represent a causal relationship. To reveal the potential causal associations between blood metabolites and PCa risk, we conducted a comprehensive two-sample Mendelian randomization (MR) analysis. We used genetic instruments for 514 and 490 metabolites from two independent comprehensive genome-wide association studies. These studies included 14,295 individuals of European ancestry from the INTERVAL/EPIC-Norfolk cohorts and 8299 individuals of European ancestry from the Canadian Longitudinal Study on Aging cohort. Summary statistics of PCa risk involving 122,188 cases and 604,640 controls of European ancestry individuals were analyzed. The associations between metabolites and PCa risk were evaluated using the inverse-variance weighted method, supplemented by sensitivity analyses including MR-Egger and MR-PRESSO tests. Additionally, we conducted a phenome-wide MR analysis to assess the potential side effects of targeting the identified metabolites for PCa intervention. Our analysis revealed 107 unique blood metabolites significantly associated with PCa risk, with 43 of these associations consistently replicated using instruments from two independent data sets. This study provides novel insights into the potential role of specific metabolites in the etiology of PCa, which warrants further investigations.