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1.
Gene ; 927: 148719, 2024 Jun 23.
Article in English | MEDLINE | ID: mdl-38917875

ABSTRACT

Renal cell carcinoma (RCC) represents a significant portion of genitourinary cancers, marked by challenging prognosis and high metastasis rates. Immunotherapy has been applied in managing advanced renal cell carcinoma, but the therapeutic outcomes are unsatisfactory. In this study, we order to construct a Janus kinase/signal transduction and activator transcriptional (JAK/STAT)-related signature linked to kidney patient outcomes for better predicting the efficacy to immune checkpoint inhibitors (ICIs) and to provide guidance for effective combination therapy. We screened 25 differentially expressed genes (DEGs) that exhibited high expression in RCC samples and were enriched in the JAK-STAT signaling pathway. Among these genes, 11 key genes were identified and correlated with the expectation of Kidney Clear Cell Carcinoma (KIRC) patients and all these genes was significantly elevated in RCC tumor tissues and cancer cells compared to para-cancer tissues and normal renal cells. Utilizing these 11 genes, we divided RCC patients into high-risk and low-risk groups. We found a clear correlation between the clinicopathologic factors of KIRC patients and the JAK-STAT-related risk score. And the IHC results shown that the JAK3 and STAT4 expression of tumor was significantly higher than normal tissue in RCC patients, the level of JAK3 and STAT4 was positively related to the T stage of RCC patients. In addition, high-risk patients had a poorer prognosis and greater protumor immune cell infiltration, and benefitted less from immunotherapy than did low-risk patients. Furthermore, the JAK-STAT-related risk score can predict disease-free survival (DFS) in RCC patients according to the nomogram, which constructed in combination with other clinical features such as age, TNM-staging and stage. Our study demonstrated the JAK-STAT signaling pathway's important regulatory function in RCC tumor immunity. This insight not only enhances our ability to accurately predict the survival rate of RCC patients, but also underscores a potential therapeutic alternative for RCC, involving the combined targeting of the JAK-STAT pathway and immune checkpoints.

2.
Br J Haematol ; 204(4): 1307-1324, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38462771

ABSTRACT

Multiple myeloma (MM) is the second most common malignant haematological disease with a poor prognosis. The limit therapeutic progress has been made in MM patients with cancer relapse, necessitating deeper research into the molecular mechanisms underlying its occurrence and development. A genome-wide CRISPR-Cas9 loss-of-function screening was utilized to identify potential therapeutic targets in our research. We revealed that COQ2 plays a crucial role in regulating MM cell proliferation and lipid peroxidation (LPO). Knockout of COQ2 inhibited cell proliferation, induced cell cycle arrest and reduced tumour growth in vivo. Mechanistically, COQ2 promoted the activation of the MEK/ERK cascade, which in turn stabilized and activated MYC protein. Moreover, we found that COQ2-deficient MM cells increased sensitivity to the LPO activator, RSL3. Using an inhibitor targeting COQ2 by 4-CBA enhanced the sensitivity to RSL3 in primary CD138+ myeloma cells and in a xenograft mouse model. Nevertheless, co-treatment of 4-CBA and RSL3 induced cell death in bortezomib-resistant MM cells. Together, our findings suggest that COQ2 promotes cell proliferation and tumour growth through the activation of the MEK/ERK/MYC axis and targeting COQ2 could enhance the sensitivity to ferroptosis in MM cells, which may be a promising therapeutic strategy for the treatment of MM patients.


Subject(s)
Multiple Myeloma , Animals , Humans , Mice , Cell Line, Tumor , Cell Proliferation , CRISPR-Cas Systems , Disease Models, Animal , Lipid Peroxidation , Mitogen-Activated Protein Kinase Kinases/therapeutic use , Multiple Myeloma/drug therapy
3.
J Transl Med ; 22(1): 133, 2024 02 03.
Article in English | MEDLINE | ID: mdl-38310229

ABSTRACT

BACKGROUND: Oxaliplatin resistance usually leads to therapeutic failure and poor prognosis in colorectal cancer (CRC), while the underlying mechanisms are not yet fully understood. Metabolic reprogramming is strongly linked to drug resistance, however, the role and mechanism of metabolic reprogramming in oxaliplatin resistance remain unclear. Here, we aim to explore the functions and mechanisms of purine metabolism on the oxaliplatin-induced apoptosis of CRC. METHODS: An oxaliplatin-resistant CRC cell line was generated, and untargeted metabolomics analysis was conducted. The inosine 5'-monophosphate dehydrogenase type II (IMPDH2) expression in CRC cell lines was determined by quantitative real-time polymerase chain reaction (qPCR) and western blotting analysis. The effects of IMPDH2 overexpression, knockdown and pharmacological inhibition on oxaliplatin resistance in CRC were assessed by flow cytometry analysis of cell apoptosis in vivo and in vitro. RESULTS: Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced apoptosis. Overexpression of IMPDH2 in CRC cells resulted in reduced cell death upon treatment with oxaliplatin, whereas knockdown of IMPDH2 led to increased sensitivity to oxaliplatin through influencing the activation of the Caspase 7/8/9 and PARP1 proteins on cell apoptosis. Targeted inhibition of IMPDH2 by mycophenolic acid (MPA) or mycophenolate mofetil (MMF) enhanced cell apoptosis in vitro and decreased in vivo tumour burden when combined with oxaliplatin treatment. Mechanistically, the Wnt/ß-catenin signalling was hyperactivated in oxaliplatin-resistant CRC cells, and a reciprocal positive regulatory mechanism existed between Wnt/ß-catenin and IMPDH2. Blocking the Wnt/ß-catenin pathway could resensitize resistant cells to oxaliplatin, which could be restored by the addition of GMP. CONCLUSIONS: IMPDH2 is a predictive biomarker and therapeutic target for oxaliplatin resistance in CRC.


Subject(s)
Colorectal Neoplasms , beta Catenin , Humans , Apoptosis , beta Catenin/metabolism , Cell Line, Tumor , Cell Proliferation , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , IMP Dehydrogenase/genetics , IMP Dehydrogenase/metabolism , Oxaliplatin/pharmacology , Oxaliplatin/therapeutic use , Oxidoreductases/genetics , Oxidoreductases/metabolism , Wnt Signaling Pathway
4.
Mol Biotechnol ; 66(3): 475-488, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37213025

ABSTRACT

Cuproptosis is a type of programmed cell death triggered by accumulation of intracellular copper which was considered closely related to tumor progression. The study of cuproptosis in multiple myeloma (MM) is however limited. To determine the prognostic significance of cuproptosis-related gene signature in MM, we interrogated gene expression and overall survival with other available clinical variables from public datasets. Four cuproptosis-related genes were included to establish a prognostic survival model by least absolute shrinkage and selection operator (LASSO) Cox regression analysis, which showed a good performance on prognosis prediction in both training and validation cohorts. Patients with higher cuproptosis-related risk score (CRRS) exhibited worse prognosis compared with lower risk score. Survival prediction capacity and clinical benefit were elevated after integrating CRRS to existing prognostic stratification system (International Staging System, ISS or Revised International Staging System, RISS) both on 3-year and 5-year survival. Based on CRRS groups, functional enrichment analysis and immune infiltration in bone marrow microenvironment revealed correlation between CRRS and immunosuppression. In conclusion, our study found that cuproptosis-related gene signature is an independent poor prognostic factor and functions negatively on immune microenvironment, which provides another perspective on prognosis assessment and immunotherapy strategy in MM.


Subject(s)
Multiple Myeloma , Humans , Multiple Myeloma/genetics , Prognosis , Immunosuppression Therapy , Immunotherapy , Apoptosis , Tumor Microenvironment/genetics
5.
Int J Med Sci ; 20(11): 1448-1459, 2023.
Article in English | MEDLINE | ID: mdl-37790849

ABSTRACT

TJP1, an adaptor protein of the adhesive barrier, has been found to exhibit distinct oncogenic or tumor suppressor functions in a cell-type dependent manner. However, the role of TJP1 in kidney renal clear cell carcinoma (KIRC) remains to be explored. The results showed a marked down-regulation of TJP1 in KIRC tissues compared to normal tissues. Low expression of TJP1 was significantly associated with high grade and poor prognosis in KIRC. Autophagosome aggregation and LC3 II conversion demonstrated that TJP1 may induce autophagy signaling in 786-O and OS-RC-2 cells. Knockdown of TJP1 led to a decrease in the expression of autophagy-related genes, such as BECN1, ATG3, and ATG7. Consistently, TJP1 expression showed a significant positive correlation with these autophagy-related genes in KIRC patients. Furthermore, the overall survival analysis of KIRC patients based on the expression of autophagy-related genes revealed that most of these genes were associated with a good prognosis. TJP1 overexpression significantly suppressed cell proliferation and tumor growth in 786-O cells, whereas the addition of an autophagy inhibitor diminished its inhibitory function. Taken together, these results suggest that TJP1 serves as a favorable prognostic marker and induces autophagy to suppress cell proliferation and tumor growth in KIRC.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Zonula Occludens-1 Protein , Autophagy/genetics , Carcinoma, Renal Cell/genetics , Cell Proliferation/genetics , Kidney Neoplasms/genetics , Kidney , Prognosis
6.
Br J Haematol ; 202(4): 840-855, 2023 08.
Article in English | MEDLINE | ID: mdl-37365680

ABSTRACT

Multiple myeloma (MM) is the second most common haematological malignancy. Despite the development of new drugs and treatments in recent years, the therapeutic outcomes of patients are not satisfactory. It is necessary to further investigate the molecular mechanism underlying MM progression. Herein, we found that high E2F2 expression was correlated with poor overall survival and advanced clinical stages in MM patients. Gain- and loss-of-function studies showed that E2F2 inhibited cell adhesion and consequently activated cell epithelial-to-mesenchymal transition (EMT) and migration. Further experiments revealed that E2F2 interacted with the PECAM1 promoter to suppress its transcriptional activity. The E2F2-knockdown-mediated promotion of cell adhesion was significantly reversed by the repression of PECAM1 expression. Finally, we observed that silencing E2F2 significantly inhibited viability and tumour progression in MM cell models and xenograft mouse models respectively. This study demonstrates that E2F2 plays a vital role as a tumour accelerator by inhibiting PECAM1-dependent cell adhesion and accelerating MM cell proliferation. Therefore, E2F2 may serve as a potential independent prognostic marker and therapeutic target for MM.


Subject(s)
Multiple Myeloma , Humans , Animals , Mice , Multiple Myeloma/genetics , Platelet Endothelial Cell Adhesion Molecule-1/genetics , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Cell Adhesion/genetics , Cell Line, Tumor , Gene Expression Regulation , Cell Proliferation , E2F2 Transcription Factor/genetics , E2F2 Transcription Factor/metabolism
7.
Transl Oncol ; 32: 101666, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37031603

ABSTRACT

Tight junction protein 1 (TJP1) is a recently identified prominent regulator of bladder cancer (BLCA) angiogenesis and tumorigenesis. Vascular mimicry (VM) is a newly described tumor feature and is correlated with an increased risk of tumor metastasis. However, the relationship between TJP1 expression and VM in bladder cancer remains elusive. In the present study, we report a novel function for TJP1 in accommodating VM to promote tumor progression. We found that the elevated TJP1 expression was positively related to VM in patients and xenograft tumor models in bladder cancer. Enforced expression of TJP1 increased VM of BLCA cells in vitro and in vivo by elevating Vascular endothelial growth factor A (VEGFA) levels. Furthermore, VM induced by TJP1 overexpression was significantly blocked by the VEGFA and VEGFR inhibitors (Bevacizumab and Sunitinib). Mechanistically, TJP1 promoted VEGFA transcriptional and protein level in a TWIST1-dependent manner. Taken together, our study reveals that TJP1-regulated VEGFA overexpression may indicate a potential therapeutic target for clinical intervention in the early tumor neovascularization of bladder cancer.

8.
Adv Sci (Weinh) ; 10(15): e2204592, 2023 05.
Article in English | MEDLINE | ID: mdl-37017573

ABSTRACT

As major regulators on bone formation/resorption in response to mechanical stimuli, osteocytes have shown great promise for restoring bone injury. However, due to the unmanageable and unabiding cell functions in unloading or diseased environments, the efficacy of osteogenic induction by osteocytes has been enormously limited. Herein, a facile method of oscillating fluid flow (OFF) loading for cell culture is reported, which enables osteocytes to initiate only osteogenesis and not the osteolysis process. After OFF loading, multiple and sufficient soluble mediators are produced in osteocytes, and the collected osteocyte lysates invariably induce robust osteoblastic differentiation and proliferation while restraining osteoclast generation and activity under unloading or pathological conditions. Mechanistic studies confirm that elevated glycolysis and activation of the ERK1/2 and Wnt/ß-catenin pathways are the major contributors to the initiation of osteoinduction functions induced by osteocytes. Moreover, an osteocyte lysate-based hydrogel is designed to establish a stockpile of "active osteocytes" to sustainably deliver bioactive proteins, resulting in accelerated healing through regulation of endogenous osteoblast/osteoclast homeostasis.


Subject(s)
Bone Resorption , Osteoclasts , Humans , Osteoclasts/metabolism , Osteoclasts/pathology , Osteocytes/metabolism , Hydrogels/metabolism , Osteoblasts/metabolism , Bone Resorption/metabolism , Bone Resorption/pathology , Homeostasis
9.
Med Oncol ; 40(4): 115, 2023 Mar 10.
Article in English | MEDLINE | ID: mdl-36897488

ABSTRACT

RUNX2 is a transcription factor that participates in osteoblast differentiation and chondrocyte maturation and plays an important role in the invasion and metastasis of cancers. With the deepening of research, evidence has indicated the correlation between RUNX2 and bone destruction in cancers. However, the mechanisms underlying its role in multiple myeloma remain unclear. By observing the induction effects of conditioned medium from myeloma cells on preosteoblasts (MC3T3-E1) and preosteoclasts (RAW264.7) and constructing myeloma-bearing mice, we found that RUNX2 promotes bone destruction in multiple myeloma. In vitro, conditioned medium from RUNX2-overexpressing myeloma cells reduced osteoblast activity and increased osteoclast activity. In vivo, RUNX2 expression was positively correlated with bone loss in myeloma-bearing mice. These results suggest that therapeutic inhibition of RUNX2 may protect against bone destruction by maintaining the balance between osteoblast and osteoclast activity in multiple myeloma.


Subject(s)
Core Binding Factor Alpha 1 Subunit , Multiple Myeloma , Osteoclasts , Animals , Mice , Cell Differentiation , Core Binding Factor Alpha 1 Subunit/metabolism , Core Binding Factor Alpha 1 Subunit/pharmacology , Culture Media, Conditioned/metabolism , Multiple Myeloma/metabolism , Osteoblasts/metabolism , Humans
10.
Oncogene ; 41(4): 502-514, 2022 01.
Article in English | MEDLINE | ID: mdl-34782718

ABSTRACT

Bladder cancer (BLCA) is the most common malignant tumor of the urinary system and is characterized by high metastatic rates and poor prognosis. The expression of tight junction protein 1 (TJP1) is associated with bladder cancer invasion; however, the mechanism by which TJP1 affects vasculature remodeling remains unknown. In this study, we found that TJP1 expression correlated with tumor angiogenesis and poor overall survival in clinical samples. Furthermore, TJP1 overexpression promoted tumor angiogenesis in BLCA cells and stimulated recruitment of macrophages to tumors by upregulating CCL2 expression. Mechanistically, TJP1 interacted with TWIST1 and enhanced the transcriptional activity of CCL2. The impairment of tumor angiogenesis caused by knockdown of TJP1 was dramatically rescued by overexpression of TWIST1. Furthermore, TJP1 recruited USP2, which deubiquitinated TWIST1, thereby protecting TWIST1 from proteasome-mediated protein degradation. In conclusion, our results suggest that TJP1 controls angiogenesis in BLCA via TWIST1-dependent regulation of CCL2. We demonstrate that TJP1 functions as a scaffold for the interaction between USP2 and TWIST1 and this may provide potential therapeutic targets in bladder cancer.


Subject(s)
Ubiquitin Thiolesterase/metabolism , Urinary Bladder Neoplasms/genetics , Zonula Occludens-1 Protein/metabolism , Animals , Cell Line, Tumor , Disease Models, Animal , Humans , Mice , Mice, Nude , Transfection , Urinary Bladder Neoplasms/pathology
11.
J Cell Mol Med ; 25(18): 8836-8849, 2021 09.
Article in English | MEDLINE | ID: mdl-34378321

ABSTRACT

Colorectal cancer (CRC) is the third most malignant tumour worldwide, with high mortality and recurrence. Chemoresistance is one of the main factors leading to metastasis and poor prognosis in advanced CRC patients. By analysing the Gene Expression Omnibus data set, we found higher hexokinase 2 (HK2) expression levels in patients with metastatic CRC than in those with primary CRC. Moreover, we observed higher enrichment in oxaliplatin resistance-related gene sets in metastatic CRC than in primary CRC. However, the underlying relationship has not yet been elucidated. In our study, HK2 expression was significantly elevated in CRC patients. Gene set enrichment analysis (GSEA) revealed multi-drug resistance and epithelial-mesenchymal transition (EMT) pathways related to high HK2 expression. Our results showed that knockdown of HK2 significantly inhibited vimentin and Twist1 expression and promoted TJP1 and E-cadherin expression in CRC cells. Additionally, transcriptional and enzymatic inhibition of HK2 by 3-bromopyruvate (3-bp) impaired oxaliplatin resistance in vitro and in vivo. Mechanistically, HK2 interacts with and stabilized Twist1 by preventing its ubiquitin-mediated degradation, which is related to oxaliplatin resistance, in CRC cells. Overexpression of Twist1 reduced the apoptosis rate by HK2 knockdown in CRC cells. Collectively, we discovered that HK2 is a crucial regulator that mediates oxaliplatin resistance through Twist1. These findings identify HK2 and Twist1 as promising drug targets for CRC chemoresistance.


Subject(s)
Colorectal Neoplasms/drug therapy , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , Hexokinase/metabolism , Nuclear Proteins/metabolism , Oxaliplatin/pharmacology , Twist-Related Protein 1/metabolism , Animals , Cell Line, Tumor , Humans , Mice , Mice, Inbred BALB C
12.
Mol Ther Oncolytics ; 19: 197-207, 2020 Dec 16.
Article in English | MEDLINE | ID: mdl-33251332

ABSTRACT

The molecular alterations that initiate the development of multiple myeloma (MM) are not fully understood. Our results revealed that TJP1 was downregulated in MM and positively related to the overall survival of MM patients in The Cancer Genome Atlas (TCGA) database and patient samples. In parallel, cell adhesion capacity representing MM metastasis was decreased in MM patients compared with healthy samples, together with the significantly activated epithelial-to-mesenchymal transition (EMT) transcriptional-like patterns of MM cells. Further analyses demonstrated that TJP1 negatively regulated EMT and consequently positively regulated cell adhesion in MM from TCGA database and MM1s cells. Furthermore, the methylation level of each CpG site on the TJP1 promoter was negatively correlated with TJP1 expression levels. Quantitative real-time PCR and western blot assays demonstrated that methylase DNMT1 regulated the methylation of TJP1. Finally, treatment with a combination of the MM clinical medicine bortezomib, methylation inhibitor, or TJP1 overexpression significantly suppressed the viability and progression of tumor cells of MM orthotopic models. In summary, our results indicate that DNMT1 promotes the methylation of TJP1 promoter, thereby decreasing its expression and regulating the development of EMT-inhibited MM cell adhesion. Therefore, methylation of TJP1 is a potential therapeutic agent to prevent the progression of MM disease.

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