Pleiotropic Regulation of PGC-1α in Tumor Initiation and Progression.

Mitochondria are recognized as a central metabolic hub with bioenergetic, biosynthetic, and signaling functions that tightly control key cellular processes. As a crucial component of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is involved in regulating various metabolic pathways, including energy metabolism and ROS homeostasis. Recent studies have highlighted the significant role of PGC-1α in tumorigenesis, cancer progression, and treatment resistance. However, PGC-1α exhibits pleiotropic effects in different cancer types, necessitating a more comprehensive and thorough understanding. In this review, we discuss the structure and regulatory mechanisms of PGC-1α, analyze its cellular and metabolic functions, explore its impact on tumorigenesis, and propose potential strategies for targeting PGC-1α. The targeted adjustment of PGC-1α based on the metabolic preferences of different cancer types could offer a hopeful therapeutic approach for both preventing and treating tumors.

Stromal interaction molecule 1/microtubule-associated protein 1A/1B-light chain 3B complex induces metastasis of hepatocellular carcinoma by promoting autophagy.

Metastasis is the leading cause of death in hepatocellular carcinoma (HCC) patients, and autophagy plays a crucial role in this process by orchestrating epithelial-mesenchymal transition (EMT). Stromal interaction molecule 1 (STIM1), a central regulator of store-operated calcium entry (SOCE) in nonexcitable cells, is involved in the development and spread of HCC. However, the impact of STIM1 on autophagy regulation during HCC metastasis remains unclear. Here, we demonstrate that STIM1 is temporally regulated during autophagy-induced EMT in HCC cells, and knocking out (KO) STIM1 significantly reduces both autophagy and EMT. Interestingly, STIM1 enhances autophagy through both SOCE-dependent and independent pathways. Mechanistically, STIM1 directly interacts with microtubule-associated protein 1A/1B-light chain 3B (LC3B) to form a complex via the sterile-α motif (SAM) domain, which promotes autophagosome formation. Furthermore, deletion of the SAM domain of STIM1 abolishes its binding with LC3B, leading to a decrease in autophagy and EMT in HCC cells. These findings unveil a novel mechanism by which the STIM1/LC3B complex mediates autophagy and EMT in HCC cells, highlighting a potential target for preventing HCC metastasis.

Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are crucial mediators of tumor-associated immune suppression. Targeting the accumulation and activation of MDSCs has been recognized as a promising approach to enhance the effectiveness of immunotherapies for different types of cancer. METHODS: The MC38 and B16 tumor-bearing mouse models were established to investigate the role of Fgl2 during tumor progression. Fgl2 and FcγRIIB-deficient mice, adoptive cell transfer, RNA-sequencing and flow cytometry analysis were used to assess the role of Fgl2 on immunosuppressive activity and differentiation of MDSCs. RESULTS: Here, we show that fibrinogen-like protein 2 (Fgl2) regulates the differentiation and immunosuppressive functions of MDSCs. The absence of Fgl2 leads to an increase in antitumor CD8+ T-cell responses and a decrease in granulocytic MDSC accumulation. The regulation mechanism involves Fgl2 modulating cholesterol metabolism, which promotes the accumulation of MDSCs and immunosuppression through the production of reactive oxygen species and activation of XBP1 signaling. Inhibition of Fgl2 or cholesterol metabolism in MDSCs reduces their immunosuppressive activity and enhances differentiation. Targeting Fgl2 could potentially enhance the therapeutic efficacy of anti-PD-1 antibody in immunotherapy. CONCLUSION: These results suggest that Fgl2 plays a role in promoting immune suppression by modulating cholesterol metabolism and targeting Fgl2 combined with PD-1 checkpoint blockade provides a promising therapeutic strategy for antitumor therapy.

Mitochondrial dynamics in health and disease: mechanisms and potential targets.

Mitochondria are organelles that are able to adjust and respond to different stressors and metabolic needs within a cell, showcasing their plasticity and dynamic nature. These abilities allow them to effectively coordinate various cellular functions. Mitochondrial dynamics refers to the changing process of fission, fusion, mitophagy and transport, which is crucial for optimal function in signal transduction and metabolism. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular fate, and a range of diseases, including neurodegenerative disorders, metabolic diseases, cardiovascular diseases and cancers. Herein, we review the mechanism of mitochondrial dynamics, and its impacts on cellular function. We also delve into the changes that occur in mitochondrial dynamics during health and disease, and offer novel perspectives on how to target the modulation of mitochondrial dynamics.

Myeloid-derived suppressor cells deficient in cholesterol biosynthesis promote tumor immune evasion.

Cancer immunotherapy targeting myeloid-derived suppressor cells (MDSCs) is one of the most promising anticancer strategies. Metabolic reprogramming is vital for MDSC activation, however, the regulatory mechanisms of cholesterol metabolic reprogramming in MDSCs remains largely unexplored. Using the receptor-interacting protein kinase 3 (RIPK3)-deficient MDSC model, a previously established tumor-infiltrating MDSC-like model, we found that the cholesterol accumulation was significantly decreased in these cells. Moreover, the phosphorylated AKT-mTORC1 signaling was reduced, and downstream SREBP2-HMGCR-mediated cholesterol synthesis was blunted. Interestingly, cholesterol deficiency profoundly elevated the immunosuppressive activity of MDSCs. Mechanistically, cholesterol elimination induced nuclear accumulation of LXRß, thereby promoting LXRß-RXRα heterodimer binding of a novel composite element in the promoter of Arg1. Furthermore, itraconazole enhanced the immunosuppressive activity of MDSCs to boost tumor growth by suppressing the RIPK3-AKT-mTORC1 pathway and impeding cholesterol synthesis. Our findings demonstrate that RIPK3 deficiency leads to cholesterol abrogation in MDSCs, which facilitates tumor-infiltrating MDSC activation, and highlight the therapeutic potential of targeting cholesterol synthesis to overcome tumor immune evasion.

A real-world analysis of survival and cost-effectiveness of sintilimab plus bevacizumab biosimilar regimen in patients with advanced hepatocellular carcinoma.

PURPOSE: Programmed death-1 (PD-1) inhibitor sintilimab plus bevacizumab has been approved as the first-line treatment for patients with advanced hepatocellular carcinoma (aHCC). However, the clinical benefits of sintilimab plus bevacizumab in a real-world setting in China is insufficiently defined to date. This study aims to evaluate the efficacy and cost-effectiveness of sintilimab plus bevacizumab biosimilar in a real-word cohort of patients with aHCC from China. METHODS: We reviewed the clinical data of 112 consecutive patients with aHCC who received sintilimab plus bevacizumab as a first-line treatment in Chongqing University Cancer hospital between July, 2021 and December, 2022. Overall survival, progression-free survival, overall response rate, and adverse event rates were assessed based on the RECIST 1.1. The survival curves were grafted by Kaplan-Meier method. RESULTS: Sixty-eight patients with aHCC were included our study. Efficacy evaluation results showed that 8 patients were partial remission, 51 patients were stable and 9 patients showed progression disease. Median overall survival and progression-free survival were 344.00 (168.77-419.23) days and 238.00 (174.56-301.44) days, respectively. Adverse events occurred in 35 patients (51.5%), including 9 patients with grade ≥ 3. The life-year (LY) and quality-adjusted LY (QALY) were 1.97 and 2.92, respectively, with a cost of $35,018. CONCLUSION: Our data confirmed the promising efficacy, tolerable toxicity and cost-effectiveness in Chinese patients with aHCC who received sintilimab plus bevacizumab as the first-line therapy regimen in real-world practice.

Equivalent carbon number-based targeted odd-chain fatty acyl lipidomics reveals triacylglycerol profiling in clinical colon cancer.

Odd-chain FAs (OCFAs) are present in very low level at nearly 1% of total FAs in human plasma, and thus, their functions were usually ignored. Recent epidemiological studies have shown that OCFAs are inversely associated with a variety of disease risks. However, the contribution of OCFAs incorporated into complex lipids remains elusive. Here, we developed a targeted odd-chain fatty acyl-containing lipidomics method based on equivalent carbon number and retention time prediction. The method displayed good reproducibility and robustness as shown by peak width at half height within 0.7 min and coefficient of variation under 20%. A total number of 776 lipid species with odd-chain fatty acyl residues could be detected in the ESI mode of reverse-phase LC-MS, of which 309 lipids were further validated using multiple reaction monitoring transitions. Using this method, we quantified odd-chain fatty acyl-containing lipidome in tissues from 12 colon cancer patients, revealing the remodeling of triacylglycerol. The dynamics of odd-chain fatty acyl lipids were further consolidated by the association with genomic and proteomic features of altered catabolism of branched-chain amino acids and triacylglycerol endogenous synthesis in colon cancer. This lipidomics approach will be applicable for screening of dysregulated odd-chain fatty acyl lipids, which enriches and improves the methods for diagnosis and prognosis evaluation of cancer using lipidomics.

OIT3 mediates macrophage polarization and facilitates hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality; however, effective immunotherapy strategies are limited because of the immunosuppressive tumor microenvironment. Macrophages are essential components of the HCC microenvironment and are related to poor prognosis. Here, we evaluated the attributes of paracancer tissues in tumor immunity and progression using public databases. Based on the abundance of immune cells estimated by CIBERSORT, we performed weighted gene co-expression network analysis and found a specific module associated with M2 macrophages. Through analyzing interaction networks using Cytoscape and public datasets, we identified oncoprotein-induced transcript 3 (OIT3) as a novel marker of M2 macrophages. Overexpression of OIT3 remodeled immune features and reprogrammed the metabolism of M2 macrophages. Moreover, compared with wildtype macrophages, OIT3-overexpressing macrophages further enhanced the migration and invasion of co-cultured cancer cells. Additionally, OIT3-overexpressing macrophages promoted tumorigenesis and cancer development in vivo. Taken together, the findings demonstrate that OIT3 is a novel biomarker of alternatively activated macrophages and facilitates HCC metastasis.

Stabilization of SETD3 by deubiquitinase USP27 enhances cell proliferation and hepatocellular carcinoma progression.

The histone methyltransferase SETD3 plays critical roles in various biological events, and its dysregulation is often associated with human diseases including cancer. However, the underlying regulatory mechanism remains elusive. Here, we reported that ubiquitin-specific peptidase 27 (USP27) promotes tumor cell growth by specifically interacting with SETD3, negatively regulating its ubiquitination, and enhancing its stability. Inhibition of USP27 expression led to the downregulation of SETD3 protein level, the blockade of the cell proliferation and tumorigenesis of hepatocellular carcinoma (HCC) cells. In addition, we found that USP27 and SETD3 expression is positively correlated in HCC tissues. Notably, higher expression of USP27 and SETD3 predicts a worse survival in HCC patients. Collectively, these data elucidated that a USP27-dependent mechanism controls SETD3 protein levels and facilitates its oncogenic role in liver tumorigenesis.

FcγRIIB potentiates differentiation of myeloid-derived suppressor cells to mediate tumor immunoescape.

Background: FcγRIIB, the sole inhibitory receptor of the Fc gamma receptor family, plays pivotal roles in innate and adaptive immune responses. However, the expression and function of FcγRIIB in myeloid-derived suppressor cells (MDSCs) remains unknown. This study aimed to investigate whether and how FcγRIIB regulates the immunosuppressive activity of MDSCs during cancer development. Methods: The MC38 and B16-F10 tumor-bearing mouse models were established to investigate the role of FcγRIIB during tumor progression. FcγRIIB-deficient mice, adoptive cell transfer, mRNA-sequencing and flow cytometry analysis were used to assess the role of FcγRIIB on immunosuppressive activity and differentiation of MDSCs. Results: Here we show that FcγRIIB was upregulated in tumor-infiltrated MDSCs. FcγRIIB-deficient mice showed decreased accumulation of MDSCs in the tumor microenvironment (TME) compared with wild-type mice. FcγRIIB was required for the differentiation and immunosuppressive activity of MDSCs. Mechanistically, tumor cell-derived granulocyte-macrophage colony stimulating factor (GM-CSF) increased the expression of FcγRIIB on hematopoietic progenitor cells (HPCs) by activating specificity protein 1 (Sp1), subsequently FcγRIIB promoted the generation of MDSCs from HPCs via Stat3 signaling. Furthermore, blockade of Sp1 dampened MDSC differentiation and infiltration in the TME and enhanced the anti-tumor therapeutic efficacy of gemcitabine. Conclusion: These results uncover an unrecognized regulatory role of the FcγRIIB in abnormal differentiation of MDSCs during cancer development and suggest a potential therapeutic target for anti-tumor therapy.

Integrated LC-MS metabolomics with dual derivatization for quantification of FFAs in fecal samples of hepatocellular carcinoma patients.

FFAs display pleiotropic functions in human diseases. Short-chain FAs (SCFAs), medium-chain FAs, and long-chain FAs are derived from different origins, and precise quantification of these FFAs is critical for revealing their roles in biological processes. However, accessing stable isotope-labeled internal standards is difficult, and different chain lengths of FFAs challenge the chromatographic coverage. Here, we developed a metabolomics strategy to analyze FFAs based on isotope-free LC-MS-multiple reaction monitoring integrated with dual derivatization. Samples and dual derivatization internal standards were synthesized using 2-dimethylaminoethylamine or dansyl hydrazine as a "light" label and N,N-diethyl ethylene diamine or N,N-diethyldansulfonyl hydrazide as a "heavy" label under mild and efficient reaction conditions. General multiple reaction monitoring parameters were designed to analyze these FFAs. The limit of detection of SCFAs varied from 0.5 to 3 nM. Furthermore, we show that this approach exhibits good linearity (R2 = 0.99374-0.99929), there is no serious substrate interference, and no quench steps are required, confirming the feasibility and reliability of the method. Using this method, we successfully quantified 15 types of SCFAs in fecal samples from hepatocellular carcinoma patients and healthy individuals; among these, propionate, butyrate, isobutyrate, and 2-methylbutyrate were significantly decreased in the hepatocellular carcinoma group compared with the healthy control group. These results indicate that the integrated LC-MS metabolomics with isotope-free and dual derivatization is an efficient approach for quantifying FFAs, which may be useful for identifying lipid biomarkers of cancer.

Inflammation and tumor progression: signaling pathways and targeted intervention.

Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates tumor progression and treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells (DCs) and antigen presentation, leading to anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK); inflammatory factors, including cytokines (e.g., interleukin (IL), interferon (IFN), and tumor necrosis factor (TNF)-α), chemokines (e.g., C-C motif chemokine ligands (CCLs) and C-X-C motif chemokine ligands (CXCLs)), growth factors (e.g., vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-ß), and inflammasome; as well as inflammatory metabolites including prostaglandins, leukotrienes, thromboxane, and specialized proresolving mediators (SPM), have been identified as pivotal regulators of the initiation and resolution of inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, and SPM have been developed to specifically modulate inflammation in cancer therapy, with some of these factors already undergoing clinical trials. Herein, we discuss the initiation and resolution of inflammation, the crosstalk between tumor development and inflammatory processes. We also highlight potential targets for harnessing inflammation in the treatment of cancer.

FGF19/SOCE/NFATc2 signaling circuit facilitates the self-renewal of liver cancer stem cells.

Background & Aims: Liver cancer stem cells (LCSCs) mediate therapeutic resistance and correlate with poor outcomes in patients with hepatocellular carcinoma (HCC). Fibroblast growth factor (FGF)-19 is a crucial oncogenic driver gene in HCC and correlates with poor prognosis. However, whether FGF19 signaling regulates the self-renewal of LCSCs is unknown. Methods: LCSCs were enriched by serum-free suspension. Self-renewal of LCSCs were characterized by sphere formation assay, clonogenicity assay, sorafenib resistance assay and tumorigenic potential assays. Ca2+ image was employed to determine the intracellular concentration of Ca2+. Gain- and loss-of function studies were applied to explore the role of FGF19 signaling in the self-renewal of LCSCs. Results: FGF19 was up-regulated in LCSCs, and positively correlated with certain self-renewal related genes in HCC. Silencing FGF19 suppressed self-renewal of LCSCs, whereas overexpressing FGF19 facilitated CSCs-like properties via activation of FGF receptor (FGFR)-4 in none-LCSCs. Mechanistically, FGF19/FGFR4 signaling stimulated store-operated Ca2+ entry (SOCE) through both the PLCγ and ERK1/2 pathways. Subsequently, SOCE-calcineurin signaling promoted the activation and translocation of nuclear factors of activated T cells (NFAT)-c2, which transcriptionally activated the expression of stemness-related genes (e.g., NANOG, OCT4 and SOX2), as well as FGF19. Furthermore, blockade of FGF19/FGFR4-NFATc2 signaling observably suppressed the self-renewal of LCSCs. Conclusions: FGF19/FGFR4 axis promotes the self-renewal of LCSCs via activating SOCE/NFATc2 pathway; in turn, NFATc2 transcriptionally activates FGF19 expression. Targeting this signaling circuit represents a potential strategy for improving the therapeutic efficacy of HCC.

Dabigatran activates inflammation resolution by promoting fibrinogen-like protein 2 shedding and RvD5n-3 DPA production.

Rationale: The interaction between coagulation and inflammation resolution remains elusive. We recently highlighted a link between fibrinogen-like protein 2 (Fgl2) and a specialized pro-resolving mediator (SPM)-n-3 docosapentaenoic acid-derived resolvin D5 (RvD5n-3 DPA) in sepsis. This study aimed to investigate the functions of commonly used anticoagulants warfarin, dabigatran and heparin in regulating inflammation resolution. Methods: Peripheral blood was collected from clinical sepsis patients and healthy control for the determination of indicated indexes. Mouse sepsis models of zymosan-induced peritonitis and cecal ligation and puncture (CLP) were employed for the measurement of inflammation- and coagulation-related indexes. Western-blotting, ELISA and flow cytometry were applied to assess proteins. UPLC-MS/MS was used to evaluate lipid metabolites. Results: Here we report that the transmembrane Fgl2 (mFgl2) was positively associated with coagulation, while soluble Fgl2 (sFgl2) level correlated with the enhanced number of peripheral blood mononuclear cells in the sepsis patients. The anticoagulants dabigatran and warfarin attenuated zymosan-induced peritonitis, which was not shared by heparin, while only dabigatran significantly improved sepsis survival in the CLP sepsis mouse model. Although these anticoagulants consistently inhibited pro-inflammatory mediators including prostaglandin E2 and leukotriene B4, only dabigatran increased sFgl2 at both the initiation and resolution phases of inflammation. Mechanistically, dabigatran elicited the shedding of sFgl2 via prothrombin-related metalloproteases, thereby enhanced the subsequent biosynthesis of RvD5n-3 DPAvia STAT6-ALOX15 axis. Blocking metalloproteases or ALOX15 significantly impaired dabigatran-enhanced macrophage efferocytosis in vitro, as well as delayed the dabigatran-accelerated inflammation resolution in vivo. Conclusions: Our findings identify the dual anti-inflammatory and pro-resolving actions of dabigatran, through promoting sFgl2-triggered RvD5n-3 DPA production, which has important implications for promoting tissue homeostasis of sepsis.

Cancer metabolism and intervention therapy.

Metabolic reprogramming with heterogeneity is a hallmark of cancer and is at the basis of malignant behaviors. It supports the proliferation and metastasis of tumor cells according to the low nutrition and hypoxic microenvironment. Tumor cells frantically grab energy sources (such as glucose, fatty acids, and glutamine) from different pathways to produce a variety of biomass to meet their material needs via enhanced synthetic pathways, including aerobic glycolysis, glutaminolysis, fatty acid synthesis (FAS), and pentose phosphate pathway (PPP). To survive from stress conditions (e.g., metastasis, irradiation, or chemotherapy), tumor cells have to reprogram their metabolism from biomass production towards the generation of abundant adenosine triphosphate (ATP) and antioxidants. In addition, cancer cells remodel the microenvironment through metabolites, promoting an immunosuppressive microenvironment. Herein, we discuss how the metabolism is reprogrammed in cancer cells and how the tumor microenvironment is educated via the metabolic products. We also highlight potential metabolic targets for cancer therapies.

RNase T2 in Inflammation and Cancer: Immunological and Biological Views.

The RNase T2 family consists of evolutionarily conserved endonucleases that express in many different species, including animals, plants, protozoans, bacteria, and viruses. The main biological roles of these ribonucleases are cleaving or degrading RNA substrates. They preferentially cleave single-stranded RNA molecules between purine and uridine residues to generate two nucleotide fragments with 2'3'-cyclic phosphate adenosine/guanosine terminus and uridine residue, respectively. Accumulating studies have revealed that RNase T2 is critical for the pathophysiology of inflammation and cancer. In this review, we introduce the distribution, structure, and functions of RNase T2, its differential roles in inflammation and cancer, and the perspective for its research and related applications in medicine.

An NAD+-Dependent Deacetylase SIRT7 Promotes HCC Development Through Deacetylation of USP39.

Ubiquitin specific protease 39 (USP39), an ortholog of Sad1p in yeast, is essential for spliceosome assembly during pre-mRNA splicing in human. Although it is known that USP39 is upregulated and plays an oncogenic role in hepatocellular carcinoma (HCC), the underlying mechanism remains unknown. The results of this study demonstrated that USP39 can be acetylated by the histone acetyltransferase MYST1, which is required for its proteasome-mediated degradation by Von Hippel-Lindau protein. In HCC cells, USP39 interacts with and is deacetylated by the lysine deacetylase sirtuin 7 (SIRT7). Notably, the deacetylation of USP39 by SIRT7 promotes its stability and thereby accelerates HCC cell proliferation and tumorigenesis in vitro and in vivo. Our data demonstrated a novel mechanism by which SIRT7 modulates the deacetylation of USP39 to promote HCC development, thus providing an effective anti-tumor therapeutic strategy for HCC.

STIM1 is a metabolic checkpoint regulating the invasion and metastasis of hepatocellular carcinoma.

Background: Cancer cells undergoing invasion and metastasis possess a phenotype with attenuated glycolysis, but enhanced fatty acid oxidation (FAO). Calcium (Ca2+)-mediated signaling pathways are implicated in tumor metastasis and metabolism regulation. Stromal-interaction molecule 1 (STIM1) triggered store-operated Ca2+ entry (SOCE) is the major route of Ca2+ influx for non-excitable cells including hepatocellular carcinoma (HCC) cells. However, whether and how STIM1 regulates the invasion and metastasis of HCC via metabolic reprogramming is unclear. Methods: The expressions of STIM1 and Snail1 in the HCC tissues and cells were measured by immunohistochemistry, Western-blotting and quantitative PCR. STIM1 knockout-HCC cells were generated by CRISPR-Cas9, and gene-overexpression was mediated via lentivirus transfection. Besides, the invasive and metastatic activities of HCC cells were assessed by transwell assay, anoikis rate in vitro and lung metastasis in vivo. Seahorse energy analysis and micro-array were used to evaluate the glucose and lipid metabolism. Results: STIM1 was down-regulated in metastatic HCC cells rather than in proliferating HCC cells, and low STIM1 levels were associated with poor outcome of HCC patients. During tumor growth, STIM1 stabilized Snail1 protein by activating the CaMKII/AKT/GSK-3ß pathway. Subsequently, the upregulated Snail1 suppressed STIM1/SOCE during metastasis. STIM1 restoration significantly diminished anoikis-resistance and metastasis induced by Snail1. Mechanistically, the downregulated STIM1 shifted the anabolic/catabolic balance, i.e., from aerobic glycolysis towards AMPK-activated fatty acid oxidation (FAO), which contributed to Snail1-driven metastasis and anoikis-resistance. Conclusions: Our data provide the molecular basis that STIM1 orchestrates invasion and metastasis via reprogramming HCC metabolism.

The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer.

BACKGROUND: Ovarian cancer is the most lethal gynecologic cancer. Chemoresistance, especially platinum-resistance, is closely related to metastasis of ovarian cancer, however, the molecular basis by which links chemoresistance and metastasis remains vague. Disordered arachidonic acid (AA) metabolism has been shown to play an important role in the advanced ovarian cancer. This study aimed to explore the underlying mechanism involving eicosanoid metabolism that controlling chemoresistance and metastasis of ovarian cancer. METHODS: Cisplatin (DDP)-resistant SKOV3 (SKOV3-R) cells were constantly induced. Ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was performed to determine the AA metabolism in SKOV3 and SKOV3-R cells. Half maximal inhibitory concentration (IC50) and percentage of cell viability were tested using cell counting kit 8 (CCK-8). Realtime quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to evaluate indicated genes and proteins respectively. Bioinformatic analysis and chromatin immunoprecipitation (ChIP) were performed to predict and identify the co-transcription factor of interest genes. Tumor growth and metastasis in the liver were assessed with nude mice by subcutaneously injection of SKOV3-R cells. RESULTS: SKOV3-R cells expressed higher multidrug resistance-associated proteins (MRPs) MRP1 and MRP4. They showed enhanced metastatic ability and produced increased AA-derived eicosanoids. Mechanistically, MRPs, epithelial mesenchymal transition (EMT) markers Snail and Slug, as well as key enzymes involved in AA-metabolism including 12-lipoxygenase (12LOX) were transcribed by the mutual transcription factor SP1 which was consistently upregulated in SKOV3-R cells. Inhibition of SP1 or 12LOX sensitized SKOV3-R cells to DDP and impaired metastasis in vitro and in vivo. CONCLUSION: Our results reveal that SP1-12LOX axis signaling plays a key role in DDP-resistance and metastasis, which provide a new therapeutic target for ovarian cancer.