Predicting the prognosis of hepatic arterial infusion chemotherapy in hepatocellular carcinoma.

Hepatic artery infusion chemotherapy (HAIC) has good clinical efficacy in the treatment of advanced hepatocellular carcinoma (HCC); however, its efficacy varies. This review summarized the ability of various markers to predict the efficacy of HAIC and provided a reference for clinical applications. As of October 25, 2023, 51 articles have been retrieved based on keyword predictions and HAIC. Sixteen eligible articles were selected for inclusion in this study. Comprehensive literature analysis found that methods used to predict the efficacy of HAIC include serological testing, gene testing, and imaging testing. The above indicators and their combined forms showed excellent predictive effects in retrospective studies. This review summarized the strategies currently used to predict the efficacy of HAIC in middle and advanced HCC, analyzed each marker's ability to predict HAIC efficacy, and provided a reference for the clinical application of the prediction system.

Circ_0000376 regulates miR-577/HK2/LDHA signaling pathway to promote the growth, invasion and glycolysis of osteosarcoma.

BACKGROUND: Many studies have confirmed that circular RNAs (circRNAs) mediate the malignant progression of various tumors including osteosarcoma (OS). Our study is to uncover novel molecular mechanisms by which circ_0000376 regulates OS progression. METHODS: The expression of circ_0000376, microRNA (miR)-577, hexokinase 2 (HK2) and lactate dehydrogenase-A (LDHA) was determined by quantitative real-time PCR. OS cell proliferation, apoptosis and invasion were measured using cell counting kit 8 assay, colony formation assay, EdU assay, flow cytometry and transwell assay. Besides, cell glycolysis was assessed by testing glucose consumption, lactate production, and ATP/ADP ratios. Protein expression was examined by western blot analysis. The interaction between miR-577 and circ_0000376 or HK2/LADA was verified by dual-luciferase reporter assay. The role of circ_0000376 on OS tumor growth was explored by constructing mice xenograft models. RESULTS: Circ_0000376 had been found to be upregulated in OS tissues and cells. Functional experiments revealed that circ_0000376 interference hindered OS cell growth, invasion and glycolysis. Circ_0000376 sponged miR-577 to reduce its expression. In rescue experiments, miR-577 inhibitor abolished the regulation of circ_0000376 knockdown on OS cell functions. MiR-577 could target HK2 and LDHA in OS cells. MiR-577 suppressed OS cell growth, invasion and glycolysis, and these effects were reversed by HK2 and LDHA overexpression. Also, HK2 and LDHA expression could be regulated by circ_0000376. In vivo experiments showed that circ_0000376 knockdown inhibited OS tumorigenesis. CONCLUSION: Circ_0000376 contributed to OS growth, invasion and glycolysis depending on the regulation of miR-577/HK2/LDHA axis, providing a potential target for OS treatment.

Latent space search based multimodal optimization with personalized edge-network biomarker for multi-purpose early disease prediction.

Considering that cancer is resulting from the comutation of several essential genes of individual patients, researchers have begun to focus on identifying personalized edge-network biomarkers (PEBs) using personalized edge-network analysis for clinical practice. However, most of existing methods ignored the optimization of PEBs when multimodal biomarkers exist in multi-purpose early disease prediction (MPEDP). To solve this problem, this study proposes a novel model (MMPDENB-RBM) that combines personalized dynamic edge-network biomarkers (PDENB) theory, multimodal optimization strategy and latent space search scheme to identify biomarkers with different configurations of PDENB modules (i.e. to effectively identify multimodal PDENBs). The application to the three largest cancer omics datasets from The Cancer Genome Atlas database (i.e. breast invasive carcinoma, lung squamous cell carcinoma and lung adenocarcinoma) showed that the MMPDENB-RBM model could more effectively predict critical cancer state compared with other advanced methods. And, our model had better convergence, diversity and multimodal property as well as effective optimization ability compared with the other state-of-art methods. Particularly, multimodal PDENBs identified were more enriched with different functional biomarkers simultaneously, such as tissue-specific synthetic lethality edge-biomarkers including cancer driver genes and disease marker genes. Importantly, as our aim, these multimodal biomarkers can perform diverse biological and biomedical significances for drug target screen, survival risk assessment and novel biomedical sight as the expected multi-purpose of personalized early disease prediction. In summary, the present study provides multimodal property of PDENBs, especially the therapeutic biomarkers with more biological significances, which can help with MPEDP of individual cancer patients.

M2 Microglia Extracellular Vesicle miR-124 Regulates Neural Stem Cell Differentiation in Ischemic Stroke via AAK1/NOTCH.

BACKGROUND: Small extracellular vesicles (sEVs) derived from M2 microglia (M2-microglia-derived small extracellular vesicles [M2-sEVs]) contribute to central nervous system repair, although the underlying mechanism remains unknown. In this study, we aimed to identify the mechanism through which microRNA-124 (miR-124) carried in sEVs promotes neural stem cell (NSC) proliferation and neuronal differentiation in the ischemic mouse brain. METHODS: M2-sEVs with or without miR-124 knockdown were injected intravenously for 7 consecutive days after transient middle cerebral artery occlusion surgery. The atrophy volume, neurological score, and degree of neurogenesis were examined at different time points after ischemic attack. NSCs treated with different sEVs were subjected to proteomic analysis. Target protein concentrations were quantified, and subsequent bioinformatic analysis was conducted to explore the key signaling pathways. RESULTS: M2-sEV transplantation promoted functional neurological recovery following transient middle cerebral artery occlusion injury. M2-sEV treatment decreased the brain atrophy volume, neurological score, and mortality rate. The effect was reserved by knockdown of miR-124 in M2-sEVs. M2-sEVs promoted proliferation and differentiation of mature neuronal NSCs in vivo. Proteomic analysis of NSC samples treated with M2-sEVs with and without miR-124 knockdown revealed that AAK1 (adaptor-associated protein kinase 1) was the key responding protein in NSCs. The binding of AAK1 to Notch promoted the differentiation of NSCs into neurons rather than astrocytes. CONCLUSIONS: Our data suggest that AAK1/Notch is the key pathway in NSCs that responds to the miR-124 carried within M2-sEVs in the ischemic brain. M2-sEVs carrying ample quantities of miR-124 promote functional recovery after ischemic stroke by enhancing NSC proliferation and differentiation. Targeting of M2-sEVs could represent a potential therapeutic strategy for brain recovery.

Multi-modal optimization to identify personalized biomarkers for disease prediction of individual patients with cancer.

Finding personalized biomarkers for disease prediction of patients with cancer remains a massive challenge in precision medicine. Most methods focus on one subnetwork or module as a network biomarker; however, this ignores the early warning capabilities of other modules with different configurations of biomarkers (i.e. multi-modal personalized biomarkers). Identifying such modules would not only predict disease but also provide effective therapeutic drug target information for individual patients. To solve this problem, we developed a novel model (denoted multi-modal personalized dynamic network biomarkers (MMPDNB)) based on a multi-modal optimization mechanism and personalized dynamic network biomarker (PDNB) theory, which can provide multiple modules of personalized biomarkers and unveil their multi-modal properties. Using the genomics data of patients with breast or lung cancer from The Cancer Genome Atlas database, we validated the effectiveness of the MMPDNB model. The experimental results showed that compared with other advanced methods, MMPDNB can more effectively predict the critical state with the highest early warning signal score during cancer development. Furthermore, MMPDNB more significantly identified PDNBs containing driver and biomarker genes specific to cancer tissues. More importantly, we validated the biological significance of multi-modal PDNBs, which could provide effective drug targets of individual patients as well as markers for predicting early warning signals of the critical disease state. In conclusion, multi-modal optimization is an effective method to identify PDNBs and offers a new perspective for understanding tumor heterogeneity in cancer precision medicine.

Osteocyte CIITA aggravates osteolytic bone lesions in myeloma.

Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast-mediated bone resorption and reduction of osteoblast-mediated bone formation. However, the molecular mechanisms underlying the differentiation and activity of osteoclasts and osteoblasts within a myelomatous microenvironment remain unclear. Here, we demonstrate that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions. CIITA upregulates the secretion of osteolytic cytokines from osteocytes through acetylation at histone 3 lysine 14 in the promoter of TNFSF11 (encoding RANKL) and SOST (encoding sclerostin), leading to enhanced osteoclastogenesis and decreased osteoblastogenesis. In turn, myeloma cell-secreted 2-deoxy-D-ribose, the product of thymidine catalyzed by the function of thymidine phosphorylase, upregulates CIITA expression in osteocytes through the STAT1/IRF1 signaling pathway. Our work thus broadens the understanding of myeloma-induced osteolysis and indicates a potential strategy for disrupting tumor-osteocyte interaction to prevent or treat patients with myeloma bone disease.

Network Control Models With Personalized Genomics Data for Understanding Tumor Heterogeneity in Cancer.

Due to rapid development of high-throughput sequencing and biotechnology, it has brought new opportunities and challenges in developing efficient computational methods for exploring personalized genomics data of cancer patients. Because of the high-dimension and small sample size characteristics of these personalized genomics data, it is difficult for excavating effective information by using traditional statistical methods. In the past few years, network control methods have been proposed to solve networked system with high-dimension and small sample size. Researchers have made progress in the design and optimization of network control principles. However, there are few studies comprehensively surveying network control methods to analyze the biomolecular network data of individual patients. To address this problem, here we comprehensively surveyed complex network control methods on personalized omics data for understanding tumor heterogeneity in precision medicine of individual patients with cancer.

Cucurbitacin E Triggers Cellular Senescence in Colon Cancer Cells via Regulating the miR-371b-5p/TFAP4 Signaling Pathway.

The induction of cellular senescence is considered as a potent strategy to suppress cancer progression. Cucurbitacin E (CE) belongs to the triterpenoids and has received substantial attention for its antineoplastic property. However, the function of CE on cellular senescence remained elusive. Herein, we revealed that CE significantly induced cellular senescence in colorectal cancer (CRC) cells. The CE effects on the cellular senescence in CRC cells were confirmed by observing the common features of the senescence, such as the enhanced activity of senescence-associated ß-galactosidase, γ-H2AX positive staining, and upregulation of senescence-associated proteins including p53, p27, and p21. Moreover, CE exerted pro-senescent effects in CRC cells via attenuating the transcription factor activating enhancer-binding protein 4 (TFAP4) expression, and the ectopic expression of TFAP4 blocked the CE-induced senescence. Mechanistically, CE treatment caused a robust increase in miR-371b-5p, which markedly repressed TFAP4. In contrast, silencing of miR-371b-5p counteracted the percentages of CE-induced senescent cells from 37.49 ± 2.61 to 7.06 ± 0.91% in HCT-116 cells via derepressing TFAP4 to attenuate the expression of p53, p21, and p16. Altogether, these results demonstrated that dietary CE induces CRC cellular senescence via modulating the miR-371b-5p/TFAP4 axis and presents opportunities for potential therapeutic strategies against CRC.

Induction of m6A methylation in adipocyte exosomal LncRNAs mediates myeloma drug resistance.

BACKGROUND: Therapeutic resistance occurs in most patients with multiple myeloma (MM). One of the key mechanisms for MM drug resistance comes from the interaction between MM cells and adipocytes that inhibits drug-induced apoptosis in MM cells; MM cells reprogram adipocytes to morph into different characterizations, including exosomes, which are important for tumor-stroma cellular communication. However, the mechanism by which exosomes mediate the cellular machinery of the vicious cycle between MM cells and adipocytes remains unclear. METHODS: Adipocytes were either isolated from bone marrow aspirates of healthy donors or MM patients or derived from mesenchymal stem cells. Co-culturing normal adipocytes with MM cells was used to generate MM-associated adipocytes. Exosomes were collected from the culture medium of adipocytes. Annexin V-binding and TUNEL assays were performed to assess MM cell apoptosis. Methyltransferase activity assay and dot blotting were used to access the m6A methylation activity of methyltransferase like 7A (METTL7A). RIP, MeRIP-seq, and RNA-protein pull down for assessing the interaction between long non-cording RNAs (LncRNAs) and RNA binding proteins were performed. Adipocyte-specific enhancer of zeste homolog 2 (EZH2) knockout mice and MM-xenografted mice were used for evaluating MM therapeutic response in vivo. RESULTS: Exosomes collected from MM patient adipocytes protect MM cells from chemotherapy-induced apoptosis. Two LncRNAs in particular, LOC606724 and SNHG1, are significantly upregulated in MM cells after exposure to adipocyte exosomes. The raised LncRNA levels in MM cells are positively correlated to worse outcomes in patients, indicating their clinical relevancy in MM. The functional roles of adipocyte exosomal LOC606724 or SNHG1 in inhibition of MM cell apoptosis are determined by knockdown in adipocytes or overexpression in MM cells. We discovered the interactions between LncRNAs and RNA binding proteins and identified methyltransferase like 7A (METTL7A) as an RNA methyltransferase. MM cells promote LncRNA package into adipocyte exosomes through METTL7A-mediated LncRNA m6A methylation. Exposure of adipocytes to MM cells enhances METTL7A activity in m6A methylation through EZH2-mediated protein methylation. CONCLUSION: This study elucidates an unexplored mechanism of how adipocyte-rich microenvironment exacerbates MM therapeutic resistance and indicates a potential strategy to improve therapeutic efficacy by blocking this vicious exosome-mediated cycle.

Montelukast attenuates interleukin IL-1ß-induced oxidative stress and apoptosis in chondrocytes by inhibiting CYSLTR1 (Cysteinyl Leukotriene Receptor 1) and activating KLF2 (Kruppel Like Factor 2).

Montelukast is a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist widely used to suppress the inflammatory response in asthma and allergic rhinitis. This study aimed to investigate the potential impacts of montelukast on osteoarthritis (OA) progression. To determine the role of montelukast in OA, the expression of CysLTR1 was first examined by quantitative reverse transcription PCR (RT-qPCR) and western blot in IL-1ß-induced ATDC5 cells treated with or without montelukast. Subsequently, the impacts of montelukast on cell viability and oxidative stress were measured by Cell-Counting-Kit-8 (CCK-8), commercial kits and western blot. Oxidative stress-related protein expressions were determined by western blot analysis in Il-1ß-induced ATDC5 cells. Cell apoptosis and cartilage degradation were examined by TdT-mediated dUTP Nick-End Labeling (TUNEL) assay, western blot and RT-qPCR. KLF2 expression was measured in IL-1ß-induced ATDC5 cells treated with montelukast. After interference with small interfering RNA (siRNA)-KLF2 in ATDC5 cells, the loss-of-function assays were also performed in same ways. CysLTR1 expression was elevated in IL-1ß-induced ATDC5 cells but inhibited significantly by montelukast. Montelukast attenuated the oxidative stress and apoptosis, improved cell viability. Moreover, montelukast enhanced KLF2 expression. After transfected with siRNA-KLF2, montelukast attenuated cell injury, oxidative stress, apoptosis and cartilage degradation in IL-1ß-induced ATDC5 cells by activating KLF2.In summary, this work elaborates the evidence that montelukast could attenuate oxidative stress and apoptosis in IL-1ß-induced chondrocytes by inhibiting CysLTR1 and activating KLF2, which can guide the therapeutic strategies of montelukast for OA development in the future.

Promotion of Bone Lesions Through the Myeloma Integrin α6-Mediated Osteolytic Signaling.

Osteolytic destruction is a hallmark of multiple myeloma and impairs myeloma patients' quality of life. However, the molecular mechanism underlying the pathogenesis of myeloma-associated bone disease remains unclear. In this study, we demonstrate the role of myeloma cell-expressed integrin α6 in bone. Integrin α6 binds to laminin 8 and epidermal growth factor receptor on mesenchymal stem cells (MSCs) to form a trimer complex and upregulates the secretion of osteolytic cytokines from both myeloma cells and MSCs, leading to enhanced bone resorption and reduced bone formation. Thus, this study elucidates an important mechanism for myeloma-induced bone lesions and implicates that targeting integrin α6 may be a viable approach for bone healing in myeloma patients.

Acetyl-CoA Synthetase 2: A Critical Linkage in Obesity-Induced Tumorigenesis in Myeloma.

Obesity is often linked to malignancies including multiple myeloma, and the underlying mechanisms remain elusive. Here we showed that acetyl-CoA synthetase 2 (ACSS2) may be an important linker in obesity-related myeloma. ACSS2 is overexpressed in myeloma cells derived from obese patients and contributes to myeloma progression. We identified adipocyte-secreted angiotensin II as a direct cause of adiposity in increased ACSS2 expression. ACSS2 interacts with oncoprotein interferon regulatory factor 4 (IRF4), and enhances IRF4 stability and IRF4-mediated gene transcription through activation of acetylation. The importance of ACSS2 overexpression in myeloma is confirmed by the finding that an inhibitor of ACSS2 reduces myeloma growth both in vitro and in a diet-induced obese mouse model. Our findings demonstrate a key impact for obesity-induced ACSS2 on the progression of myeloma. Given the central role of ACSS2 in many tumors, this mechanism could be important to other obesity-related malignancies.

TAS-102 has a tumoricidal activity in multiple myeloma.

TAS-102/Lonsurf is a new oral anti-tumor drug consisting of trifluridine and tipiracil in a 1:0.5 molar ratio. Lonsurf has been approved globally, including US, Europe Union, and China, to treat patients with advanced colorectal cancer. Ongoing clinical trials are currently conducted for the treatment of other solid cancers. However, the therapeutic potential of TAS-102 in hematological malignancies has not been explored. In this study, we investigate the therapeutic efficacy of TAS-102 in multiple myeloma both in vitro and in vivo. We demonstrate that TAS-102 treatment inhibits tumor cell proliferation in six human myeloma cell lines with IC50 values in a range from 0.64 to 9.10 µM. Dot blotting and immunofluorescent staining show that trifluridine is predominately incorporated into genomic DNAs of myeloma cells. TAS-102 treatment induces myeloma cell apoptosis through cell cycle arrest in G1 phase and activation of cGAS-STING signaling in myeloma cells. In the human myeloma xenograft models, TAS-102 treatment reduces tumor progression and prolongs mouse survival. TAS-102 has shown its efficacies in the drug-resistant myeloma cells, and the combination of TAS-102 and bortezomib has a synergistic anti-myeloma activity. Our preclinical studies indicate that TAS-102 is a potential novel agent for myeloma therapy.

SREBP-1 inhibitor Betulin enhances the antitumor effect of Sorafenib on hepatocellular carcinoma via restricting cellular glycolytic activity.

Lipid metabolism that correlates tightly to the glucose metabolic regulation in malignant cells includes hepatocellular carcinoma (HCC) cells. The transcription factor Sterol Regulatory Element Binding Protein 1 (SREBP-1), a regulator of fatty acid synthesis, has been shown to pivotally regulate the proliferation and metastasis of HCC cells. However, the intrinsic mechanism by which SREBP-1 regulates the survival of HCC cells remains unclear. In this study, among HCC patients who had dismal responses to Sorafenib, a high SREBP-1 level was found in the tumors and correlated to poor survival. This observation suggested the negative role of SREBP-1 in clinical HCC prognosis. Our mechanistical studies reveal that the inhibition of SREBP-1 via its inhibitor Betulin suppresses cellular glucose metabolism. In addition to the reduced glycolytic activity, a thwarted metastatic potential was observed in HCC cells upon Betulin administration. Moreover, our data show that SREBP-1 inhibition facilitated the antitumor effects of Sorafenib on HCC cells and xenograft tumors.

Avenanthramide A triggers potent ROS-mediated anti-tumor effects in colorectal cancer by directly targeting DDX3.

Colorectal cancer (CRC) is a common malignant gastrointestinal tumor with high mortality worldwide. Drug resistance and cytotoxicity to normal cells are the main causes of chemotherapeutic treatment failure in CRC. Therefore, extracting the bioactive compounds from natural products with anti-carcinogenic activity and minimal side-effects is a promising strategy against CRC. The present study aims to evaluate the anti-carcinogenic properties of avenanthramides (AVNs) extracted from oats bran and clarify the underlying molecular mechanisms. We demonstrated that AVNs treatment suppressed mitochondrial bioenergetic generation, resulting in mitochondrial swelling and increased reactive oxygen species (ROS) production. Further study indicated that AVNs treatment significantly reduced DDX3 expression, an oncogenic RNA helicase highly expressed in human CRC tissues. DDX3 overexpression reversed the ROS-mediated CRC apoptosis induced by AVNs. Of note, we identified Avenanthramide A (AVN A) as the effective ingredient in AVNs extracts. AVN A blocked the ATPase activity of DDX3 and induced its degradation by directly binding to the Arg287 and Arg294 residues in DDX3. In conclusion, these innovative findings highlight that AVNs extracts, in particular its bioactive compound AVN A may crack the current hurdles in the way of CRC treatment.

Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease.

Osteolytic lesions in multiple myeloma are caused by osteoclast-mediated bone resorption and reduced bone formation. A unique feature of myeloma is a failure of bone healing after successful treatment. We observed adipocytes on trabecular bone near the resorbed area in successfully treated patients. Normal marrow adipocytes, when cocultured with myeloma cells, were reprogrammed and produced adipokines that activate osteoclastogenesis and suppress osteoblastogenesis. These adipocytes have reduced expression of peroxisome proliferator-activated receptor γ (PPARγ) mediated by recruitment of polycomb repressive complex 2 (PRC2), which modifies PPARγ promoter methylation at trimethyl lysine-27 histone H3. We confirmed the importance of methylation in the PPARγ promoter by demonstrating that adipocyte-specific knockout of EZH2, a member of the PRC2, prevents adipocyte reprogramming and reverses bone changes in a mouse model. We validated the strong correlation between the frequency of bone lesions and the expression of EZH2 in marrow adipocytes from patients in remission. These results define a role for adipocytes in genesis of myeloma-associated bone disease and that reversal of adipocyte reprogramming has therapeutic implications.

Lysosome exocytosis is involved in astrocyte ATP release after oxidative stress induced by H2O2.

BACKGROUND AND PURPOSE: Studies demonstrated that oxidative damage decreased intracellular ATP level in astrocytes. However, the pathway mediated ATP level decrease is obscure. Our previous study found intracellular ATP could be released via lysosome exocytosis in astrocytes. Here, we explored whether lysosome exocytosis was involved in ATP release during oxidative stress induced by H2O2 in astrocytes. METHODS: Astrocytes were isolated from the cortex of neonatal rats. Intracellular lysosomes and calcium signals were stained in astrocytes before and after H2O2 stimulation. ATP molecules location and ATP level were detected by immunostaining and bioluminescence method, respectively. Extracellular ß-Hexosaminidase and LDH were examined by colorimetric method. RESULTS: We found that ATP located in lysosome of astrocytes. H2O2 stimulation resulted in the decrease of lysosomes staining and the increase of extracellular ATP, compared to the control (p < 0.05). At the same time, intracellular Fluo4 signals and ß-Hexosaminidase level were also increased (p < 0.05). Extracellular LDH level did not show an increase, suggesting that there is no cell membrane damage after H2O2 stimulation. Glycyl-phenylalanine 2-naphthylamide blocked lysosome exocytosis and inhibited ATP release in astrocytes after H2O2-treatment (p < 0.05). CONCLUSION: Our results indicated that H2O2 induced ATP release from intracellular to extracellular via lysosome exocytosis. The increase of intracellular Ca2+ was necessary for lysosome release under oxidative stress induced by H2O2.

Toxicological effects of bisphenol A exposure-induced cancer cells migration via activating directly integrin ß1.

Bisphenol A (BPA) is an important chemical that widely used in our life. Mounting evidences show that BPA can leak into environment, which associates with the health risks, such as initiation and metastasis of cancer, but the mechanisms still need to be interpreted. Integrin ß1 is the most known subunit in integrin family, its abnormal expression and activation are tightly linked to tumorigenesis and a number of hallmarks of cancer. Here we show that environmental concentration (10-8 M) of BPA exposure can quickly activate integrin ß1 to induce cancer cell migration, and this effect is proved as a direct interaction between BPA and integrin ß1, which is independent from classical or non-canonical estrogen receptors. The data further indicates that residues S134, D137 and E229 in integrin ß1 played important roles in the interaction as predicted by AutoDock Vina, and confirmed by spectroscopy and native-PAGE. The study is the first to show a tumorigenic mechanism of BPA on tumor metastasis by the direct activation of integrin ß1 molecule, and give rise to profound concerns about widespread use of BPA in the manufacture of plastics and human health.

GRP78 plays an integral role in tumor cell inflammation-related migration induced by M2 macrophages.

Macrophages are the main immune-competent cells that infiltrate in tumors. Tumor-associated macrophages (TAMs), termed M2 macrophages, facilitate tumor progress and promote metastasis. However, M2 macrophages always display an immunosuppressive phenotype, which is not in accordance with the tumor inflammatory microenvironment and inflammation-related metastasis. In this study, we established a macrophage polarization model with human monocytes and found that the conditioned medium from M2 macrophages increased GRP78 expression in tumor cells and facilitated tumor cell migration. Mechanistically, excessive GRP78 formed a protein complex with STAT3 and JAK2 to promote STAT3 phosphorylation. Furthermore, p-STAT3 facilitated the high expression of inflammatory factors IL-1ß and TNF-α in tumor cells, which was important in M2 macrophage-induced metastasis. The present data demonstrate that M2 macrophages elevate tumor cell GRP78 expression to trigger an inflammatory response, which further facilitates tumor metastasis. Therefore, our study not only uncovered a new cause of GRP78 overexpression in tumor cell, but also, explained the antinomy of TAMs immunosuppressive properties and inflammation-related tumor metastasis.