Publications by authors named "Tianxiao Gao"

9 Publications

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Elevated expression of HMGB1 is prognostic of poor survival in patients with relapsed/refractory T/NK-CL.

Ann Hematol 2021 May 15. Epub 2021 May 15.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China.

Despite the clinical value of HMGB1 in non-Hodgkin lymphoma (NHL), the impact of HMGB1 protein expression on survival of patients with mature T-cell and NK-cell lymphoma (T/NK-CL) is unknown. Here, we evaluated correlations of HMGB1 expression in tumor tissues with pathophysiological characteristics of disease and determined the prognostic value of HMGB1 expression in relapsed/refractory T/NK-CL. HMGB1 expression was detected by immunohistochemistry (IHC) in 66 cases of relapsed/refractory T/NK-CL, and specimens were classified as high or low HMGB1 expression. Univariate and multivariate Cox regression analyses identified prognostic factors associated with progression-free survival (PFS) and overall survival (OS). High HMGB1 expression was significantly correlated with increased Ki67 levels and progressive lymphoma subtypes. Univariate Cox regression analysis showed that high HMGB1 expression was associated with unfavorable PFS (P = 0.006) and poorer OS (P < 0.001). Prognostic factors identified by univariate analysis were prognostic index for peripheral T-cell lymphoma non-specified (PIT) score ≥ 2, bone marrow involvement, Ki67 ≥ 70%, and high HMGB1 expression. Multivariate Cox regression analysis revealed that high HMGB1 expression was an independent prognostic factor for poorer PFS [hazard ratio (HR) 3.593; 95% confidence interval (CI) 1.171-11.027; P = 0.025] and OS [HR 7.663; 95% CI 2.367-24.803; P = 0.001]. A proposal prognostic model combining HMGB1 and Ki67 expression showed improved prognostic capacity and may help guide treatment planning. High HMGB1 expression may be a promising prognostic predictor and a potential therapeutic target for relapsed/refractory T/NK-CL. Furthermore, to apply HMGB1 as one of the best bio-maker, an external independent control cohort is needed.
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http://dx.doi.org/10.1007/s00277-021-04473-4DOI Listing
May 2021

PEDF inhibits lymphatic metastasis of nasopharyngeal carcinoma as a new lymphangiogenesis inhibitor.

Cell Death Dis 2021 03 17;12(4):295. Epub 2021 Mar 17.

Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

Nasopharyngeal carcinoma (NPC) is one of the most malignant tumors in southern China and Asia, and lymph node metastasis is an important cause for treatment failure. Lymphangiogenesis is a crucial step in lymphatic metastasis of NPC, while little is known about lymphangiogenesis in NPC. Similar to angiogenesis, lymphangitic neovascularization is a process of balance between pro-lymphangiogenesis and anti-lymphangiogenesis factors, but there are few studies on endogenous lymphangiogenesis inhibitors. Pigment epithelium-derived factor (PEDF) is a well-known effective endogenous angiogenesis inhibitor. However, the relationship between PEDF and lymphangiogenesis remains unknown. Our present study reveals that PEDF is lowly expressed in human NPC tissues with poor prognosis and is negatively correlated with lymphatic vessel density (LVD). Consistently, PEDF inhibits lymphangiogenesis and lymphatic metastasis of NPC in vivo experiments. Mechanistically, PEDF inhibits the proliferation, migration, and tube formation of lymphatic endothelial cells and promotes cell apoptosis. On the other hand, PEDF reduces the expression and secretion of vascular endothelial growth factor C (VEGF-C) of NPC cells through the nuclear factor-κB (NF-κB) signaling pathway. Our findings indicate that PEDF plays a vital role in lymphatic metastasis by targeting both lymphatic endothelial cells and NPC cells, and PEDF may represent a novel therapeutic target for NPC.
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http://dx.doi.org/10.1038/s41419-021-03583-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969934PMC
March 2021

The E3 ubiquitin ligase Peli1 regulates the metabolic actions of mTORC1 to suppress antitumor T cell responses.

EMBO J 2021 01 20;40(2):e104532. Epub 2020 Nov 20.

Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Metabolic fitness of T cells is crucial for immune responses against infections and tumorigenesis. Both the T cell receptor (TCR) signal and environmental cues contribute to the induction of T cell metabolic reprogramming, but the underlying mechanism is incompletely understood. Here, we identified the E3 ubiquitin ligase Peli1 as an important regulator of T cell metabolism and antitumor immunity. Peli1 ablation profoundly promotes tumor rejection, associated with increased tumor-infiltrating CD4 and CD8 T cells. The Peli1-deficient T cells display markedly stronger metabolic activities, particularly glycolysis, than wild-type T cells. Peli1 controls the activation of a metabolic kinase, mTORC1, stimulated by both the TCR signal and growth factors, and this function of Peli1 is mediated through regulation of the mTORC1-inhibitory proteins, TSC1 and TSC2. Peli1 mediates non-degradative ubiquitination of TSC1, thereby promoting TSC1-TSC2 dimerization and TSC2 stabilization. These results establish Peli1 as a novel regulator of mTORC1 and downstream mTORC1-mediated actions on T cell metabolism and antitumor immunity.
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http://dx.doi.org/10.15252/embj.2020104532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809702PMC
January 2021

Dual Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Inhibition Elicits Antitumor Immunity and Enhances Programmed Cell Death-1 Checkpoint Blockade in Hepatocellular Carcinoma.

Liver Cancer 2020 Jun 25;9(3):338-357. Epub 2020 Feb 25.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background And Aims: Combining anti-angiogenic therapy with immune checkpoint blockade with anti-programmed cell death-1 (PD-1) antibodies is a promising treatment for hepatocellular carcinoma (HCC). Tyrosine kinase inhibitors are well-known anti-angiogenic agents and offer potential for combination with anti-PD-1 antibodies. This study investigated the possible underlying immunomodulatory mechanisms of combined therapy.

Methods: HCC tissue samples for RNA-sequencing (RNA-seq) were obtained from patients with differential prognoses following anti-PD-1 treatment. Recombinant basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) were used to stimulate T cells following lenvatinib or sorafenib treatment, respectively. T cell function was analyzed by flow cytometry and lactate dehydrogenase assay. In vivo experiments were conducted in murine H22 and Hepa 1-6 competent models of HCC. Local immune infiltration in the tumor microenvironment (TME) was assessed using multicolor flow cytometry. Gene regulation was evaluated by RNA-seq. Microvascular density was measured by immunohistochemistry, and PD-1 ligand (PD-L1) induction was quantified by western blot.

Results: The baseline expression of VEGF and fibroblast growth factor (FGF) in patients with progressive disease was significantly higher than in patients achieving stable disease following anti-PD-1 treatment. VEGFA and bFGF significantly upregulated the expression of PD-1, cytotoxic T-lymphocyte-associated protein-4, and Tim-3 on T cells, while inhibiting the secretion of interferon gamma (IFNG) and granzyme B and suppressing T cell cytotoxicity. This immunosuppressive effect was reverted by lenvatinib but not sorafenib. Furthermore, dual lenvatinib/anti-PD-1 antibody therapy led to better antitumor effects than either sorafenib or fibroblast growth factor receptor (FGFR) inhibitor (BGJ398) in H22 murine models of HCC. Combined lenvatinib/anti-PD-1 treatment also led to long-term immune memory formation, while synergistically modulating the TME and enhancing the cytotoxic effect of T cells. Finally, lenvatinib inhibited PD-L1 expression on human umbilical vein endothelial cells, which improved the function of T cells.

Conclusions: Inhibition of vascular endothelial growth factor receptor and FGFR augmented the efficacy of anti-PD-1 antibodies. Combined lenvatinib/anti-PD-1 treatment appears to exert antitumor activity by synergistically modulating effector T cell function in the TME and by mutually regulating tumor vessel normalization.
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http://dx.doi.org/10.1159/000505695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325120PMC
June 2020

Metformin selectively inhibits metastatic colorectal cancer with the mutation by intracellular accumulation through silencing MATE1.

Proc Natl Acad Sci U S A 2020 06 22;117(23):13012-13022. Epub 2020 May 22.

Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China;

Metastatic colorectal cancer (mCRC) patients have poor overall survival despite using irinotecan- or oxaliplatin-based chemotherapy combined with anti-EGFR (epidermal growth factor receptor) drugs, especially those with the oncogene mutation of Metformin has been reported as a potentially novel antitumor agent in many experiments, but its therapeutic activity is discrepant and controversial so far. Inspiringly, the median survival time for -mutation mCRC patients with diabetes on metformin is 37.8 mo longer than those treated with other hypoglycemic drugs in combination with standard systemic therapy. In contrast, metformin could not improve the survival of mCRC patients with wild-type Interestingly, metformin is preferentially accumulated in -mutation mCRC cells, but not wild-type ones, in both primary cell cultures and patient-derived xenografts, which is in agreement with its tremendous effect in -mutation mCRC. Mechanistically, the mutated KRAS oncoprotein hypermethylates and silences the expression of multidrug and toxic compound extrusion 1 (MATE1), a specific pump that expels metformin from the tumor cells by up-regulating DNA methyltransferase 1 (DNMT1). Our findings provide evidence that -mutation mCRC patients benefit from metformin treatment and targeting MATE1 may provide a strategy to improve the anticancer response of metformin.
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http://dx.doi.org/10.1073/pnas.1918845117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293710PMC
June 2020

TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis.

Nat Cell Biol 2019 12 2;21(12):1604-1614. Epub 2019 Dec 2.

Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

TANK-binding kinase 1 (TBK1) responds to microbial stimuli and mediates the induction of type I interferon (IFN). Here, we show that TBK1 is also a central mediator of growth factor signalling; this function of TBK1 relies on a specific adaptor-TBK-binding protein 1 (TBKBP1). TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation by growth factors but not by innate immune stimuli. Although the TBK1-TBKBP1 signalling axis is not required for the induction of type I IFN, it mediates mTORC1 activation and oncogenesis. Conditional deletion of either TBK1 or TBKBP1 in lung epithelial cells inhibits tumourigenesis in a mouse model of lung cancer. In addition to promoting tumour growth, the TBK1-TBKBP1 axis facilitates tumour-mediated immunosuppression through a mechanism that involves induction of the checkpoint molecule PD-L1 and stimulation of glycolysis. These findings suggest a PKCθ-TBKBP1-TBK1 growth factor signalling axis that mediates both tumour growth and immunosuppression.
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http://dx.doi.org/10.1038/s41556-019-0429-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901116PMC
December 2019

The contrary intracellular and extracellular functions of PEDF in HCC development.

Cell Death Dis 2019 10 3;10(10):742. Epub 2019 Oct 3.

Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

Pigment epithelium-derived factor (PEDF), a classic angiogenic inhibitor, has been reported to function as a tumor suppression protein and to downregulate in many types of solid tumors. However, the expression level of PEDF and its role in hepatocellular carcinoma (HCC) are contradictory. The present study investigates the expression and different activities of secreted and intracellular PEDF during HCC development, as well as the underlying mechanism of PEDF on HCC lipid disorders. We found that PEDF had no association with patients' prognosis, although PEDF was highly expressed and inhibited angiogenesis in HCC tumor tissues. The animal experiments indicated that full-length PEDF exhibited equalizing effects on tumor growth activation and tumor angiogenesis inhibition in the late stage of HCC progression. Importantly, the pro-tumor activity was mediated by the intracellular PEDF, which causes accumulation of free fatty acids (FFAs) in vivo and in vitro. Based on the correlation analysis of PEDF and lipid metabolic indexes in human HCC tissues, we demonstrated that the intracellular PEDF led to the accumulation of FFA and eventually promoted HCC cell growth by inhibiting the activation of AMPK via ubiquitin-proteasome-mediated degradation, which causes increased de novo fatty acid synthesis and decreased FFA oxidation. Our findings revealed why elevated PEDF did not improve the patients' prognosis as the offsetting intracellular and extracellular activities. This study will lead to a comprehensive understanding of the diverse role of PEDF in HCC and provide a new selective strategy by supplement of extracellular PEDF and downregulation of intracellular PEDF for the prevention and treatment of liver cancer.
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http://dx.doi.org/10.1038/s41419-019-1976-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776659PMC
October 2019

FUBP1 promotes neuroblastoma proliferation via enhancing glycolysis-a new possible marker of malignancy for neuroblastoma.

J Exp Clin Cancer Res 2019 Sep 11;38(1):400. Epub 2019 Sep 11.

Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

Background: Neuroblastoma (NB) is one of the deadliest paediatric solid tumours due to its rapid proliferative characteristics. Amplified copies of MYCN are considered the most important marker for the prediction of tumour relapse and progression in NB, but they were only detected in 20-30% of NB patients, indicating there might be other oncogenes in the development of NB. The far upstream element binding protein 1 (FUBP1) was first identified as a transcriptional regulator of the proto-oncogene MYC. However, the expression and role of FUBP1 in NB have not been documented.

Methods: FUBP1 expression was analysed from GEO database and verified by immunohistochemistry (IHC) and western blotting (WB) in NB tissues and cell lines. Cell proliferation and apoptosis were detected by Cell Counting Kit-8, Colony formation assay, EDU, TUNEL staining and flow cytometric analysis. Several glycolytic metabolites production was confirmed by ELISA and oxygen consuming rate (OCR). Luciferase assay, WB, chromatin immunoprecipitation (CHIP) were used to explore the mechanisms of the effect of FUBP1 on NB.

Results: FUBP1 mRNA levels were increased along with the increase in International Neuroblastoma Staging System (INSS) stages. High expression of FUBP1 with low N-Myc expression accounted for 44.6% of NB patient samples (n = 65). In addition, FUBP1 protein levels were remarkably increased with NB malignancy in the NB tissue microarray (NB: n = 65; ganglioneuroblastoma: n = 31; ganglioneuroma: n = 27). Furthermore, FUBP1 expression was negatively correlated with patient survival rate but positively correlated with ki67 content. In vitro experiments showed that FUBP1 promotes NB cell proliferation and inhibits cell apoptosis via enhancing glycolysis and ATP production. Mechanistically, FUBP1 inhibited the degradation of HIF1α via downregulation of Von Hippel-Lindau (VHL), the E3 ligase for HIF1α, resulting in upregulation of lactate dehydrogenase isoform B (LDHB) expression to enhance glycolysis. Overexpressed or silenced N-Myc could not regulate FUBP1 or LDHB levels.

Conclusions: Taken together, our findings demonstrate for the first time that elevated FUBP1 promotes NB glycolysis and growth by targeting HIF1α rather than N-Myc, suggesting that FUBP1 is a novel and powerful oncogene in the development of NB independent of N-Myc and may have potential in the diagnosis and treatment of NB.
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http://dx.doi.org/10.1186/s13046-019-1414-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737630PMC
September 2019

Kallistatin inhibits lymphangiogenesis and lymphatic metastasis of gastric cancer by downregulating VEGF-C expression and secretion.

Gastric Cancer 2018 07 14;21(4):617-631. Epub 2017 Dec 14.

Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.

Background: Tumor-induced lymphangiogenesis and lymphatic metastasis are predominant during the metastasis of many types of cancers. However, the endogenous inhibitors that counterbalance the lymphangiogenesis and lymphatic metastasis of tumors have not been well evaluated. Kallistatin has been recognized as an endogenous angiogenesis inhibitor.

Methods And Results: Our recent study showed for the first time that the lymphatic vessel density (LVD) was reduced in lung and stomach sections from kallistatin-overexpressing transgenic mice. Kallistatin expresses anti-lymphangiogenic activity by inhibiting the proliferation, migration, and tube formation of human lymphatic endothelial cells (hLECs). Therefore, the present study focuses on the relationships of changes in kallistatin expression with the lymphangiogenesis and lymphatic metastasis of gastric cancer and its underlying mechanisms. Our results revealed that the expression of kallistatin in cancer tissues, metastatic lymph nodes, and plasma of gastric cancer patients was significantly downregulated and that the plasma level of kallistatin was negatively associated with the phase of lymph node metastasis. Furthermore, treatment with kallistatin recombinant protein decreased LVD and lymph node metastases in the implanted gastric xenograft tumors of nude mice. Mechanically, kallistatin suppressed the lymphangiogenesis and lymphatic metastasis by downregulating VEGF-C expression and secretion through the LRP6/IKK/IҡB/NF-ҡB signaling pathway in gastric cancer cells.

Conclusions: These findings demonstrated that kallistatin functions as an endogenous lymphangiogenesis inhibitor and has an important part in the lymphatic metastasis of gastric cancer.
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http://dx.doi.org/10.1007/s10120-017-0787-5DOI Listing
July 2018