Development Of Malignant Tumors Research Articles

P53 Pathway Inactivation Drives SMARCB1-deficient p53-wildtype Epithelioid Sarcoma Onset Indicating Therapeutic Vulnerability Through MDM2 Inhibition.

Loss of the gene SMARCB1 drives the development of malignant rhabdoid tumors, epithelioid sarcomas, and other malignancies. The SMARCB1 protein is a core component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) family of chromatin remodeling complexes, which are important regulators of gene expression and cell differentiation. Here, we use CRISPR-Cas9 to create germline smarcb1 loss of function in zebrafish. We demonstrate that the combination of smarcb1 deficiency with mutant p53 results in the development of epithelioid sarcomas, angiosarcomas, and carcinomas of the thyroid and colon. Although human epithelioid sarcomas do not frequently harbor p53 mutations, smarcb1-deficient tumors in zebrafish were only observed following disruption of p53, indicating that p53 signaling in human tumors might be attenuated through alternative mechanisms, such as MDM2-mediated proteasomal degradation of p53. To leverage this possibility for the treatment of human epithelioid sarcoma, we tested small molecule-mediated disruption of the p53-MDM2 interaction, which stabilized p53 protein leading to p53-pathway reactivation, cell-cycle arrest, and increased apoptosis. Moreover, we found that MDM2 inhibition and the topoisomerase II inhibitor doxorubicin synergize in targeting epithelioid sarcoma cell viability. This could be especially relevant for patients with epithelioid sarcoma because doxorubicin represents the current gold standard for their clinical treatment. Our results therefore warrant reactivating p53 protein in SMARCB1-deficient, p53-wildtype epithelioid sarcomas using combined doxorubicin and MDM2 inhibitor therapy.

Identification of an integrated kinase-related prognostic gene signature associated with tumor immune microenvironment in human uterine corpus endometrial carcinoma.

In the worldwide, uterine corpus endometrial carcinoma (UCEC) is the sixth most common malignancy in women, and the number of women diagnosed is increasing. Kinase plays an important role in the occurrence and development of malignant tumors. However, the research about kinase in endometrial cancer is still unclear. Here, we first downloaded the gene expression data of 552 UCEC patients and 23 healthy endometrial tissues from The Cancer Genome Atlas (TCGA), obtained 538 kinase-related genes from the previous literature, and calculated 67 differentially expressed kinases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were referenced to identify multiple important biological functions and signaling pathways related to 67 differentially expressed kinases. Using univariate Cox regression and Least absolute shrinkage and selection operator (LASSO), seven kinases (ALPK2, CAMKV, TTK, PTK6, MAST1, CIT, and FAM198B) were identified to establish a prognostic model of endometrial cancer. Then, patients were divided into high- and low-risk groups based on risk scores. Receiver operating characteristic (ROC) curves were plotted to evaluate that the model had a favorable predictive ability. Kaplan–Meier survival analysis suggested that high-risk groups experienced worse overall survival than low-risk groups. qRT-PCR and ISH assays confirmed the consistency between predicted candidate genes and real sample contents. CIBERSORT algorithm and ssGSEA were adopted to investigate the relationship between this signature and tumor immune microenvironment, and revealed that in low- and high-risk groups, the types of tumor-infiltrating immune cells and the immune cell-related functions were significantly different. In summary, a seven-gene signature risk model has been constructed, and could accurately predict the prognosis of UCEC, which may offer ideas and breakthrough points to the kinase-associated development of UCEC.

Challenges for the application of EGFR-targeting peptide GE11 in tumor diagnosis and treatment

Abnormal regulation of cell signaling pathways on cell survival, proliferation and migration contributes to the development of malignant tumors. Among them, epidermal growth factor receptor (EGFR) is one of the most important biomarkers in many types of malignant solid tumors. Its over-expression and mutation status can be served as a biomarker to identify patients who can be benifit from EGFR tyrosine kinase inhibitors and anti-EGFR monocloncal antibody (mAb) therapy. For decades, researches on EGFR targeted ligands were actively carried out to identify potent candidates for cancer therapy. An ideal EGFR ligand can competitively inhibit the binding of endogenous growth factor, such as epidermal growth factor (EGF) and transforming growth factor-α(TGF-α) to EGFR, thus block EGFR signaling pathway and downregulate EGFR expression. Alternatively, conjugation of EGFR ligands on drug delivery systems (DDS) can facilitate targeting delivery of therapeutics or diagnostic agents to EGFR over-expression tumors via EGFR-mediated endocytosis. GE11 peptide is one of the potent EGFR ligand screened from a phage display peptide library. It is a dodecapeptide that can specifically binds to EGFR with high affinity and selectivity. GE11 has been widely used in the diagnosis and targeted delivery of drugs for radiotherapy, genetherapy and chemotherpy against EGFR positive tumors. In this review, the critical factors affecting the in vivo and in vitro targeting performance of GE11 peptide, including ligand-receptor intermolecular force, linker bond properties and physiochemical properties of carrier materials, are detailedly interpreted. This review provides a valuable vision for the rational design and optimization of GE11-based active targeting strategies for cancer treatment, and it will promote the translation studies of GE11 from lab research to clinical application.

Prognostic and immune-related value of complement C1Q (C1QA, C1QB, and C1QC) in skin cutaneous melanoma.

Background: Skin cutaneous melanoma (SKCM) is a common malignancy that is associated with increased morbidity and mortality. Complement C1Q is composed of C1QA, C1QB, and C1QC and is involved in the occurrence and development of many malignant tumours. However, the effect of C1QA, C1QB, and C1QC expression on tumour immunity and prognosis of cutaneous melanoma remains unclear. Methods: First, we analysed C1QA, C1QB, and C1QC expression levels and prognostic values using Gene Expression Profiling Interactive Analysis (GEPIA) and Tumour Immune Estimation Resource (TIMER) analysis, and further validation was performed using RT-qPCR, The Human Protein Atlas, The Cancer Genome Atlas (TCGA) dataset, and Gene Expression Omnibus dataset. We then performed univariate/multivariate Cox proportional hazard model, clinicopathological correlation, and receiver operating characteristic curve analysis using TCGA dataset and established a nomogram model. Differentially expressed genes associated with C1QA, C1QB, and C1QC in SKCM were identified and analysed using LinkedOmics, TIMER, the Search Tool for the Retrieval of Interacting Genes database, and Metascape and Cytoscape software platforms. We used TIMER, GEPIA, and single-sample gene set enrichment analysis (ssGSEA) to analyse the relationship between the three genes and the level of immune cell infiltration, biomarkers, and checkpoint expression in SKCM. Finally, GSEA was utilized to study the functional pathways of C1QA, C1QB, and C1QC enrichment in SKCM. Results: The overexpression of C1QA, C1QB, and C1QC provided significant value in the diagnosis of SKCM and has been associated with better overall survival (OS). Multivariate Cox regression analysis indicated that C1QA, C1QB, and C1QC are independent prognostic biomarkers for patients with SKCM. Immune cell infiltration, biomarkers, and checkpoints were positively correlated with the expression of C1QA, C1QB, and C1QC. Furthermore, the results of functional and pathway enrichment analysis showed that immune-related and apoptotic pathways were significantly enriched in the high-expression group of C1QA, C1QB, and C1QC. Conclusion: We found that C1QA, C1QB, and C1QC can be used as biomarkers for the diagnosis and prognosis of SKCM patients. The upregulated expression levels of these three complement components benefit patients from OS and may increase the effect of immunotherapy. This result may be due to the dual effects of anti-tumour immunity and apoptosis.

Smoking and lung cancer (clinical and epidemiological study).

Annotation. Tobacco smoke is one of the dangerous exogenous factors contributing to the emergence of chronic noncommunicable diseases and, first of all, malignant tumors.
 Purpose. On the basis of the hospital cancer registry created at the N.N. Petrov National Medical Research Center of Oncology (N.N. Petrov NMRC of Oncology), to analyze the differences in the specific weights of the risk of exposure to the smoking factor on cancer patients treated in the hospital with various oncopathologies. At the population level, to consider the dynamics of morbidity and mortality of the population of Russia, the North-Western Federal District (NWFD) and St. Petersburg of lung cancer patients, taking into account the impact of the coronavirus pandemic.
 The material of the study is the created database (DB) of the hospital and population cancer registry, working according to international standards and statistical reference books of the P.A. Herzen Moscow Research Institute of Oncology (P.A. Herzen Institute of Oncology) and the N.N. Petrov NMRC of Oncology, questioning of patients in the hospital.
 Results. Of the 47,356 patients treated at the center, 9201 or 19.4% abused smoking. The highest percentage of smokers was found among patients with laryngeal cancer (C32) 66.67%, esophageal cancer (C15) 53.20% and lung cancer (C33,34) 51.08. The lowest proportion of smokers among patients diagnosed with uterine body cancer (C54) 8.8% and breast (C50) 10.1%. It was found that 52.01% of smokers smoked more than half, up to one pack of cigarettes a day.
 Conclusions. Thus, the study proved a direct link between the smoking factor and the development of malignant tumors. It was found that more than 50% of patients with lung cancer are smokers. The proportion of smoking patients for other nosologies is significantly less, with the exception of laryngeal (C32) and esophageal (C15). We also noted an increase in the number of women who smoke both in the whole group of patients and in the group of patients diagnosed with lung cancer.

Disease-related protein co-expression networks are associated with the prognosis of resectable node-positive pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a multifactorial disease, the molecular profile of which remains unclear. This study aimed at unveiling the disease-related protein networks associated with different outcomes of resectable, node-positive PDAC cases. We assessed laser-microdissected cancerous cells from PDAC tissues of a poor outcome group (POG; n = 4) and a better outcome group (BOG; n = 4). Noncancerous pancreatic duct tissues (n = 5) were used as the reference. We identified four representative network modules by applying a weighted network correlation analysis to the obtained quantitative PDAC proteome datasets. Two network modules that were significant for POG were associated with the heat shock response to hypoxia-related stress; in the latter, a large involvement of the non-canonical Hedgehog pathway (regulated by GLI1), the internal ribosome entry site-mediated cap-independent translation, the inositol requiring enzyme 1-alpha (IRE1α)/X-box binding protein 1 pathway of the unfolding protein response (UPR), and the aerobic glycolysis was observed. By contrast, the BOG characteristic module was involved in the inactivation of the UPR pathway via the synoviolin 1-dependent proteasomal degradation of IRE1α, the activation of SOX2, and the loss of PALB2 (partner and localizer of BRCA2) function, all potentially suppressing malignant tumor development. Our findings might facilitate future therapeutic strategies for PDAC.

Reversing PD-1 Resistance in B16F10 Cells and Recovering Tumour Immunity Using a COX2 Inhibitor.

Simple SummarySome patients develop drug resistance to programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1) therapy but the mechanism is unclear. Therefore, the study of drug resistance to PD-1 therapy is quite important. In this sense, we obtained B16F10-R tumours resistant to anti-PD-1 therapy through multiple rounds of drug resistance screening in vitro. We found that COX2 expression was significantly elevated and COX2 inhibitors in combination with anti-PD-1 monoclonal antibodies (mAbs) could reverse this resistance phenomenon. Knockout of the ptgs2 gene in B16F10-R tumours also restored tumour sensitivity to anti-PD-1 therapy. Therefore, we believe that the combination of COX2 inhibitors and anti-PD-1 mAbs may become a new choice for the drug resistance of anti-PD-1 therapy in the future.Immunotherapy is an effective method for tumour treatment. Anti-programmed cell death protein 1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) monoclonal antibodies play a significant role in immunotherapy of most tumours; however, some patients develop drug resistance to PD-1/PD-L1 therapy. Cyclooxygenase-2 (COX2) is expressed in various solid tumours, and prostaglandin E2 (PGE2) drives the development of malignant tumours. We developed a drug-resistant B16F10 (B16F10-R) tumour mouse model through four rounds of selection in vivo. Subsequently, we investigated changes in PD-L1 expression and lymphocyte infiltration in B16F10-NR and B16F10-R tumours. Additionally, we explored the role of COX2 in acquired resistance to pembrolizumab, an anti-PD-1 treatment. Immune cell infiltration was significantly decreased in resistant tumours compared to B16F10-NR tumours; however, ptgs2 gene expression was significantly elevated in resistant tumours. Aspirin or celecoxib combined with pembrolizumab can effectively reverse tumour drug resistance. In addition, ptgs2 knockout or the use of the EP4 inhibitor E7046 abrogated drug resistance to anti-PD-1 treatment in B16F10-R tumour cells. Our study showed that inhibition of the COX2/PGE2/EP4 axis could increase the number of immune cells infiltrating the tumour microenvironment and recover drug-resistant tumour sensitivity to pembrolizumab. Thus, we highlight COX2 inhibition as a promising therapeutic target for drug-resistant tumours for future consideration.

Recent research on the association between signal transducer and activator of transcription 5 and childhood acute lymphoblastic leukemia.

Signal transducer and activator of transcription 5 (STAT5) can be involved in the processes such as cell proliferation, differentiation, apoptosis, and hematopoiesis, and its dysregulation is closely associated with the development and progression of malignant tumors including leukemia and may affect the treatment outcome and prognosis of pediatric patients. Identification of STAT5 can facilitate targeted therapy to improve the response rate of children with acute lymphoblastic leukemia. This article reviews the impact of STAT5 on the development/progression, targeted therapy strategies and the prognosis of childhood acute lymphoblastic leukemia.

The Role of PTEN in Epithelial-Mesenchymal Transition.

Simple SummaryThe PTEN phosphatase is a ubiquitously expressed tumor suppressor, which inhibits the PI3K/AKT pathway in the cell. The PI3K/AKT pathway is considered to be one of the main signaling pathways that drives the proliferation of cancer cells. Furthermore, the same pathway controls the epithelial–mesenchymal transition (EMT). EMT is an evolutionarily conserved developmental program, which, upon aberrant reactivation, is also involved in the formation of cancer metastases. Importantly, metastasis is the leading cause of cancer-associated deaths. In this review, we discuss the literature data that highlight the role of PTEN in EMT. Based on this knowledge, we speculate about new possible strategies for cancer treatment.Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) is one of the critical tumor suppressor genes and the main negative regulator of the PI3K pathway. PTEN is frequently found to be inactivated, either partially or fully, in various malignancies. The PI3K/AKT pathway is considered to be one of the main signaling cues that drives the proliferation of cells. Perhaps it is not surprising, then, that this pathway is hyperactivated in highly proliferative tumors. Importantly, the PI3K/AKT pathway also coordinates the epithelial–mesenchymal transition (EMT), which is pivotal for the initiation of metastases and hence is regarded as an attractive target for the treatment of metastatic cancer. It was shown that PTEN suppresses EMT, although the exact mechanism of this effect is still not fully understood. This review is an attempt to systematize the published information on the role of PTEN in the development of malignant tumors, with a main focus on the regulation of the PI3K/AKT pathway in EMT.

The Knowledge and Photoprotective Behaviour of the Hungarian Population in Relation to Skin Cancer

Introduction. The carcinogenic ultraviolet range of sunlight plays a major role in the development of malignant skin tumours with a steadily increasing incidence. It shows a significant upward trend in our country, with 2,742 new cases registered in 2016, nearly 15% of which were under 40 years of age. With conscious behaviour and the use of sunscreen products, the incidence of skin tumours can be reduced. The aim of the study is to assess the Hungarian population’s knowledge about skin cancer and attitudes towards sun protection.Methods. Quantitative cross-sectional study was conducted in a dermatology clinic and among 7th and 8th-grade students and 11th and 12th-grade students of two high schools. The self-administered questionnaire used in the study included questions on socio-demographic data, addictions, skin type, family history of skin cancer, sunburns, sunbathing habits, sunscreen use, knowledge about sun protection and skin cancer, screening and self-testing.Results. 83.9% of respondents (n=356) have experien- ced sunburn 3 or more times, and 27.8% use sunscreen regularly (n=118). 62.7% of respondents (n=266) have never had a skin cancer/melanoma screening. A significant association was found between education, gender and sunscreen use (p<0.001). A significant association was also found between risky behaviour and going to a tanning salon (p<0.001).Conclusions. The Hungarian population has a lack of knowledge about skin cancer. The results indicate that more emphasis should be placed on increasing the knowledge and awareness of the population about sun protection and on developing good habits, starting at the primary and se- condary level.

Prognosis value of IL-6, IL-8, and IL-1β in serum of patients with lung cancer: A fresh look at interleukins as a biomarker

Interleukins are assumed to be closely related to the occurrence and development of human malignant tumors, while a few of them were commonly used as diagnostic markers in clinical cancer, including lung cancer. This study aimed to explore the value of serum interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) combined with carcinoembryonic antigen (CEA) as biomarker panel for the diagnosis and metastasis prediction of lung cancer. IL-1β, IL-6, IL-8, and CEA in serum were determined using electrochemiluminescence immunoassay (ECLIA) and flow cytometry, and the diagnostic value of each marker was analyzed using receiver operating characteristic (ROC) curves and logistic fitting regression. We found that the levels of serum IL-1β, IL-6, and IL-8 showed no significant difference among squamous cell carcinoma, adenocarcinoma, and small cell carcinoma, while they were significantly higher in the lung cancer group or benign group than those in the healthy group. The levels of IL-8 and CEA were positively correlated with clinical stages respectively. Importantly, the panel of CEA + IL-6 + IL-8 has the highest efficacy for the diagnosis of lung cancer (AUC = 0.883) among all the detected panels, while the panel of IL-8 + CEA showed the most promising predictive value for the lymph node metastasis (AUC = 0.686) and distant metastasis of lung cancer (AUC = 0.793). In conclusion, IL-6 and IL-8 could be used as promising molecular biomarkers to diagnose and predict the metastasis of lung cancer independent of pathological types, improving the specificity and sensitivity of diagnosis for lung cancer when they were combined with CEA.

Metabolomic Analysis Reveals that SPHK1 Promotes Oral Squamous Cell Carcinoma Progression through NF-κB Activation.

Metabolic disorders are significant in the occurrence and development of malignant tumors. Changes of specific metabolites and metabolic pathways are molecular therapeutic targets. This study aims to determine the metabolic differences between oral squamous cell carcinoma (OSCC) tissues and paired adjacent noncancerous tissues (ANT) through liquid chromatography-mass spectrometry (LC-MS). SPHK1 is a key enzyme in sphingolipid metabolism. This study also investigates the potential role of SPHK1 in OSCC. This study used LC-MS to analyze metabolic differences between OSCC tissues and paired ANT. Principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) were applied to explain the significance of phospholipid metabolism pathways in the occurrence and development of OSCC. Through further experiments, we confirmed the oncogenic phenotypes of SPHK1 in vitro and in vivo, including proliferation, migration, and invasion. The sphingolipid metabolic pathway was significantly activated in OSCC, and the key enzyme SPHK1 was significantly upregulated in oral cancer tissues, predicting poor OSCC prognosis. In this study, SPHK1 overexpression was associated with high-grade malignancy and poor OSCC prognosis. SPHK1 targeted NF-κB by facilitating p65 expression to regulate OSCC tumor progression and promote metastasis. This study identified metabolic differences between OSCC and paired ANT, explored the carcinogenic role of overexpressed SPHK1, and revealed the association of SPHK1 with poor OSCC prognosis. SPHK1 targets NF-κB signaling by facilitating p65 expression to regulate tumor progression and promote tumor metastasis, providing potential therapeutic targets for diagnosing and treating oral tumors.

Regulation of SUMOylation Targets Associated With Wnt/β-Catenin Pathway

Wnt/β-catenin signaling is a delicate and complex signal transduction pathway mediated by multiple signaling molecules, which plays a significant role in regulating human physiology and pathology. Abnormally activated Wnt/β-catenin signaling pathway plays a crucial role in promoting malignant tumor occurrence, development, recurrence, and metastasis, particularly in cancer stem cells. Studies have shown that the Wnt/β-catenin signaling pathway controls cell fate and function through the transcriptional and post-translational regulation of omics networks. Therefore, precise regulation of Wnt/β-catenin signaling as a cancer-targeting strategy may contribute to the treatment of some malignancies. SUMOylation is a post-translational modification of proteins that has been found to play a major role in the Wnt/β-catenin signaling pathway. Here, we review the complex regulation of Wnt/β-catenin signaling by SUMOylation and discuss the potential targets of SUMOylation therapy.

Knockdown and inhibition of hydroxytryptamine receptor 1D suppress proliferation and migration of gastric cancer cells

Serotonin (5-hydroxytryptamine, 5-HT) and its receptors play important roles in the development and progression of malignant tumors. The effect of the 5-HT receptor 1D (HTR1D), a member of the serotonin receptor family, on gastric cancer (GC) is not clear. Analysis of clinical data has shown that high expression of HTR1D was associated with poor prognosis in patients with GC and was an independent risk factor for reduced overall survival (OS) and disease-free survival (DFS). The present study assessed the effects of HTR1D knockdown and the HTR1D inhibitor GR127935 on the biological behavior of GC cells, which both impaired the proliferation and migration of GC cells. RNA sequencing showed that GR127935 inhibited tumor progression by limiting DNA replication and the cell cycle, inducing ferroptosis, and affecting tumor metabolism. Taken together, these findings showed that HTR1D has a potent oncogenic effect on GC and may provide a novel therapeutic target.

Prognostic Role of M6A-Associated Immune Genes and Cluster-Related Tumor Microenvironment Analysis: A Multi-Omics Practice in Stomach Adenocarcinoma

N6-methylandrostenedione (m6A) methylation plays a very important role in the development of malignant tumors. The immune system is the key point in the progression of tumors, particularly in terms of tumor treatment and drug resistance. Tumor immunotherapy has now become a hot spot and a new approach for tumor treatment. However, as far as the stomach adenocarcinoma (STAD) is concerned, the in-depth research is still a gap in the m6A-associated immune markers. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases is extremely important for our research, where we obtained gene mutation, gene expression data and relevant clinical information of STAD patients. Firstly, the samples from GEO were used as external validation groups, while the TCGA samples were divided into a training group and an internal validation group randomly. Using the way of Single factor COX-LASSO- and multi-factor Cox to construct the prognostic model. Then, all samples were subjected to cluster analysis to generate high and low expression groups of immune gene. Meanwhile, we also collected the correlation between these types and tumor microenvironment. On this basis, a web version of the dynamic nomogram APP was developed. In addition, we performed microenvironmental correlation, copy number variation and mutation analyses for model genes. The prognostic model for STAD developed here demonstrated a very strong predictive ability. The results of cluster analysis manifested that the immune gene low expression group had lower survival rate and higher degree of immune infiltration. Therefore, the immune gene low expression group was associated with lower survival rates and a higher degree of immune infiltration. Gene set enrichment analysis suggested that the potential mechanism might be related to the activation of immunosuppressive functions and multiple signaling pathways. Correspondingly, the web version of the dynamic nomogram APP produced by the DynNom package has successfully achieved rapid and accurate calculation of patient survival rates. Finally, the multi-omics analysis of model genes further enriched the research content. Interference of RAB19 was confirmed to facilitate migration of STAD cells in vitro, while its overexpression inhibited these features. The prognostic model for STAD constructed in this study is accurate and efficient based on multi-omics analysis and experimental validation. Additionally, the results of the correlation analysis between the tumor microenvironment and m6Ascore are the basics of further exploration of the pathophysiological mechanism in STAD.

The Role of P4HA1 in Multiple Cancer Types and its Potential as a Target in Renal Cell Carcinoma.

Background: Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) provides the majority of the catalytic site of the active P4H enzyme. Emerging evidence has revealed that P4HA1 participates in the initiation and development of several malignant tumors. However, a pan-cancer analysis of P4HA1 has not been performed. Methods: In this study, we carried out an in-depth analysis of the expression patterns and prognostic value of P4HA1 using the datasets of The Cancer Genome Atlas (TCGA) and Kaplan–Meier Plotter. Genomic and epigenetic alterations of P4HA1 and the correlation of P4HA1 with DNA methylation in different cancers were also analyzed across multiple databases. In addition, the purity-adjusted partial Spearman’s correlation test was utilized to evaluate the correlation between P4HA1 expression and immune cell infiltration. We also further explored the biological function and mechanism of P4HA1 in renal cell carcinoma (RCC). Results: We characterized the expression profiles and prognostic values of P4HA1 in multiple cancer types. P4HA1 expression was increased in clear cell renal cell carcinoma (RCC) compared to adjacent normal tissues, and P4HA1 positively correlated with the overall survival (OS) and disease-free survival (DFS) in papillary RCC. In addition, a positive correlation between P4HA1 expression and immune cell infiltration was observed in clear cell RCC. We also identified a strong correlation between P4HA1 expression and immune checkpoint gene expression, microsatellite instability, and tumor mutation burden in chromophobe RCC. Finally, the results of in vitro experiments verified that overexpression of P4HA1 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition of RCC cells. Conclusion: Overall, our study has suggested that P4HA1 might play a significant role in tumorigenesis in RCC and may be a prognostic biomarker and therapeutic target for several malignant tumors, including RCC.

Role of HIF-1α/ERRα in Enhancing Cancer Cell Metabolism and Promoting Resistance of Endometrial Cancer Cells to Pyroptosis

Oxygen is critical to energy metabolism, and tumors are often characterized by a hypoxic microenvironment. Owing to the high metabolic energy demand of malignant tumor cells, their survival is promoted by metabolic reprogramming in the hypoxic microenvironment, which can confer tumor cell resistance to pyroptosis. Pyroptosis resistance can inhibit anti-tumor immunity and promote the development of malignant tumors. Hypoxia inducible factor-1α (HIF-1α) is a key regulator of metabolic reprogramming in tumor cells, and estrogen-related receptor α (ERRα) plays a key role in regulating cellular energy metabolism. Therefore, the close interaction between HIF-1α and ERRα influences the metabolic and functional changes in cancer cells. In this review, we summarize the reprogramming of tumor metabolism involving HIF-1α/ERRα. We review our understanding of the role of HIF-1α/ERRα in promoting tumor growth adaptation and pyroptosis resistance, emphasize its key role in energy homeostasis, and explore the regulation of HIF-1α/ERRα in preventing and/or treating endometrial carcinoma patients. This review provides a new perspective for the study of the molecular mechanisms of metabolic changes in tumor progression.

Metabolic Reprogramming in Cancer Cells: Emerging Molecular Mechanisms and Novel Therapeutic Approaches

The constant changes in cancer cell bioenergetics are widely known as metabolic reprogramming. Reprogramming is a process mediated by multiple factors, including oncogenes, growth factors, hypoxia-induced factors, and the loss of suppressor gene function, which support malignant transformation and tumor development in addition to cell heterogeneity. Consequently, this hallmark promotes resistance to conventional anti-tumor therapies by adapting to the drastic changes in the nutrient microenvironment that these therapies entail. Therefore, it represents a revolutionary landscape during cancer progression that could be useful for developing new and improved therapeutic strategies targeting alterations in cancer cell metabolism, such as the deregulated mTOR and PI3K pathways. Understanding the complex interactions of the underlying mechanisms of metabolic reprogramming during cancer initiation and progression is an active study field. Recently, novel approaches are being used to effectively battle and eliminate malignant cells. These include biguanides, mTOR inhibitors, glutaminase inhibition, and ion channels as drug targets. This review aims to provide a general overview of metabolic reprogramming, summarise recent progress in this field, and emphasize its use as an effective therapeutic target against cancer.

Abstract 1574: LSD-germline variant drive oncogenicity

Abstract Lysosome storage disease (LSD) is a congenital metabolic disorder caused by mutations in genes involved in the function of lysosomes. Defects in the genes encoding hydrolases and transporters and enzyme activators are found in LSD’s, leading to the accumulation of macromolecules in the late endocytic system. And this disruption of lysosomal homeostasis increases the induction of endoplasmic reticulum and oxidative stress, proliferative signal transduction, extracellular matrix degradation, Integrin-β4-mediated cell migration and invasion, and consequently can promote the development of oncogenic cells and malignant tumors. It is known that the function of lysosomes is very important in cancer diseases. Recently, through a preliminary study, we found that the incidence of myeloproliferative neoplasm (MPN) increases statistically significantly when the LSD putative pathogenic germline variant (PPGV) is present. Based on this, we performed single-cell RNA (scRNA) sequencing using MPN patient samples of both LSD PPGV carrier and non-carrier. We tried to determine how the LSD PPGV affects MPN cancer progression at the single-cell level. To confirm functional differences between the two groups, DEG, pathway enrichment, LR-pair interaction, and transcription enrichment analyses were performed. In the analysis, immune cells were composed of T-cell, NK-cell, and Monocyte (in the order of frequency). It was confirmed that Lysosome-related (ER, Golgi, etc.) functions were upregulated in the carrier group compared to the non-carrier group across cell types. In addition, in the ligand-receptor (LR)-pair interaction analysis targeting Immune cells, it was possible to find a statistically significant difference (average log2 fold change>0.7 and p-value<0.05) candidate LR-pair (IL6-IL6R*IL6ST) that upregulates in the carrier group compared to the non-carrier group. The candidate LR-pair found by our team has been previously known as a cytokine-related gene that plays an inflammatory or fibrosis-related role in MPN and affects cancer progression. Also, in the Transcription Factor Enrichment analysis conducted together, it was confirmed that the statistically significant (NES>2 and FDR<0.01) candidate Transcription Factor (STAT1), which operates dependent on the candidate LR-pair, is upregulated. In conclusion, we found the possibility that genes and functions related to cancer progression can be up-regulated by LSD germline variants. In addition, we plan to conduct additional studies to determine the exact mechanism of contribution to cancer development by the LSD germline variant. Citation Format: Hyundong Yoon, Seulki Song, Yeeun Ha, Youngil Koh, SungSoo Yoon. LSD-germline variant drive oncogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1574.

Targeting TMEM88 as an Attractive Therapeutic Strategy in Malignant Tumors.

According to authoritative surveys, the overall morbidity and mortality of malignant tumors show an upward trend, and it is predicted that this trend will not be well contained in the upcoming new period. Since the influencing factors, pathogenesis, and progression characteristics of malignant tumors have not been fully elucidated, the existing treatment strategies, mainly including surgical resection, ablation therapy and chemotherapy, cannot achieve satisfactory results. Therefore, exploring potential therapeutic targets and clarifying their functions and mechanisms in continuous research and practice will provide new ideas and possibilities for the treatment of malignant tumors. Recently, a double-transmembrane protein named transmembrane protein 88 (TMEM88) was reported to regulate changes in downstream effectors by mediating different signaling pathways and was confirmed to be widely involved in cell proliferation, differentiation, apoptosis and tumor progression. At present, abnormal changes in TMEM88 have been found in breast cancer, ovarian cancer, lung cancer, thyroid cancer and other malignant tumors, which has also attracted the attention of tumor research and attempted to clarify its function and mechanism. However, due to the lack of systematic generalization, comprehensive and detailed research results have not been comprehensively summarized. In view of this, this article will describe in detail the changes in TMEM88 in the occurrence and development of malignant tumors, comprehensively summarize the corresponding molecular mechanisms, and explore the potential of targeting TMEM88 in the treatment of malignant tumors to provide valuable candidate targets and promising intervention strategies for the diagnosis and cure of malignant tumors.