Juan Li

Second Military Medical University, Shanghai, Shanghai, Shanghai Shi, China

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Publications (11)34.16 Total impact

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    ABSTRACT: Although autophagy is most critical for survival of cancer cells, especially in fast-growing tumors, the mechanism remains to be fully characterized. Herein we report that PSMD10/Gankyrin promotes autophagy in hepatocellular carcinoma (HCC) in response to starvation or stress through 2 complementary routes. PSMD10 was physically associated with ATG7 in the cytoplasm, and this association was enhanced by initial nutrient deprivation. Subsequently, PSMD10 translocated into the nucleus and bound cooperatively with nuclear HSF1 (heat shock transcription factor 1) onto the ATG7 promoter, upregulated ATG7 expression in the advanced stage of starvation. Intriguingly, the type of PSMD10-mediated autophagy was independent of the proteasome system, although PSMD10 has been believed as an indispensable chaperone for assembly of the 26S proteasome. A significant correlation between PSMD10 expression and ATG7 levels was detected in human HCC biopsies, and the combination of these 2 parameters is a powerful predictor of poor prognosis. The median survival of sorafenib-treated HCC patients with high expression of PSMD10 was much shorter than those with low expression of PSMD10. Furthermore, PSMD10 augmented autophagic flux to resist sorafenib or conventional chemotherapy, and inhibition of autophagy suppressed PSMD10-mediated resistance. These results present a novel mechanism involving modulation of ATG7 by PSMD10 in sustaining autophagy, promoting HCC cell survival against starvation or chemotherapy. Targeting of PSMD10 might therefore be an attractive strategy in HCC treatment by suppressing autophagy and inducing HCC cell sensitivity to drugs.
    No preview · Article · Apr 2015 · Autophagy
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    ABSTRACT: Toll-like receptor 4 has an important role in inflammation and immunity. Whether TLR4 signaling contributes to the link between insulin resistance and islet p cell dysfunction is an unanswered question. Here, we show that in the face of the same high-fat continuous stimulation for 24 weeks, in TLR4-/- HF mice, the weight, fraction of the liver, epididymal fat pad fraction, as well as blood glucose and insulin levels were lower than in the WT HF group. In TLR4-/- HF mice, the O-2 consumption, CO2 production and activities were higher than in the WT HF group. Glucose tolerance test, insulin tolerance test and insulin release test suggest that the impaired insulin secretion was significantly improved in TLR4-/- HF mice, compared with the WT HF group. In TLR4-/- HF mice, islet p cell ultrastructure was not damaged in the face of the same high-fat continuous stimulation, compared to that in the WT HF group. By detecting glucose-stimulated insulin secretion in the primary islet, insulin secretion of TLR4-/- HF mice was better than that of the WT HF group, and in the TLR4-/- HF group, at the mRNA level, islet interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and monocyte chemotactic protein 1 (MCP-1) were significantly lower than in the WT HF group. There was the islet macrophage infiltration in the WT HF group, but no significant macrophage infiltration in the TLR4-/- HF group. These data suggest that the damaged islet functions of the high fat diet-induced obesity mice may be linked to the TLR4 expression level, and the recruitment of macrophages into the islets.
    Preview · Article · Oct 2014 · Central-European Journal of Immunology
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    ABSTRACT: Aim: Free fatty acid-induced lipotoxicity plays a crucial role in the progression of nonalcoholic fatty liver disease (NAFLD). In the present study we investigated the effects of a high-fat diet and free fatty acids on the autophagic process in hepatocytes in vivo and in vitro and the underlying mechanisms. Methods: LC3-II expression, a hallmark of autophagic flux, was detected in liver specimens from patients with non-alcoholic steatohepatitis (NASH) as well as in the livers of C57BL/6 mice fed a high-fat diet (HFD) up to 16 weeks. LC3-II expression was also analyzed in human SMMC-7721 and HepG2 hepatoma cells exposed to palmitic acid (PA), a saturated fatty acid. PA-induced apoptosis was detected by Annexin V staining and specific cleavage of PARP in the presence and absence of different agents. Results: LC3-II expression was markedly increased in human NASH and in liver tissues of HFD-fed mice. Treatment of SMMC-7721 cells with PA increased LC3-II expression in time-and dose-dependent manners, whereas the unsaturated fatty acid oleic acid had no effect. Inhibition of autophagy with 3MA sensitized SMMC-7721 cells to PA-induced apoptosis, whereas activation of autophagy by rapamycin attenuated PA-induced PARP cleavage. The autophagy-associated proteins Beclin1 and Atg5 were essential for PA-induced autophagy in SMMC-7721 cells. Moreover, pretreatment with SP600125, an inhibitor of JNK, effectively abrogated PA-mediated autophagy and apoptosis. Specific knockdown of JNK2, but not JNK1, in SMMC-7721 cells significantly suppressed PA-induced autophagy and enhanced its pro-apoptotic activity; whereas specific knockdown of JNK1 had the converse effect. Similar results were obtained when HepG2 cells were tested. Conclusion: JNK1 promotes PA-induced lipoapoptosis, whereas JNK2 activates pro-survival autophagy and inhibits PA lipotoxicity. Our results suggest that modulation of autophagy may have therapeutic benefits in the treatment of lipid-related metabolic diseases.
    No preview · Article · Mar 2014 · Acta Pharmacologica Sinica
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    ABSTRACT: Obesity is an important inducing factor for type 2 diabetes. However, the mechanism underlying high-fat-(HF) diet-induced obesity in pancreatic beta cell dysfunction is still unclear. Toll-like receptor-4 (TLR4) is a key mediator of innate immunity. To investigate the effects of TLR4 in obesity-induced pancreatic beta cell dysfunction, we used male diabetic (db/db), obese (ob/ob) mice, TLR4-wild type (WT), and TLR4-knockout mice that were fed with normal diet or HF diet for 24 weeks. Immunostaining of TLR4 and TLR4 mRNA level in pancreatic islet were assessed. The results from biological characteristics, glucose tolerance test, insulin tolerance test, and insulin release test showed that the function of pancreatic islet was impaired in HF-fed TLR4 WT mice, but was protected in HF-fed TLR4 deficient (TLR4(-/-)) mice. By electron microscope detection, we observed that beta cell insulin secretory vesicles increased in HF-fed TLR4 WT mice. Ultrastructure of beta cell in HF-fed TLR4(-/-) mice was similar to that in normal chow diet-fed TLR4 WT mice. Then, glucose-stimulated insulin secretion assay by using primary pancreatic islet showed that the secretion function of pancreatic islet in HF-fed TLR4(-/-) mice was better than that in HF-fed TLR4 WT mice. Furthermore, in HF-fed TLR4(-/-) mice, the mRNA levels of IL-6, TNF-α, and MCP-1 genes in pancreatic islet were significantly lower than those in HF-fed TLR4 WT mice. Consistent with the change in gene expression, HF-fed TLR4 WT mice but not HF-fed TLR4(-/-) mice exhibited macrophage invasion in pancreatic island. Taken together, our data indicated that HF diet-induced obesity can stimulate the up-regulation of TLR4 locating on the surface of pancreatic beta cell, and subsequently lead to the recruitment of macrophage into pancreatic islet, which finally results in pancreatic beta cell dysfunction. This process is a possible mechanism involved in obesity-induced pancreatic beta cell dysfunction.
    Preview · Article · Aug 2013 · Acta Biochimica et Biophysica Sinica
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    ABSTRACT: Pancreatic cancer has an extremely poor prognosis mainly due to lack of effective treatment options. Radiotherapy is mostly applied to locally advanced cases, although tumor radioresistance limits the effectiveness. Profilin1, a novel tumor suppressor gene, was reported to be down-regulated in various cancers and associated with tumor progression. The objective of this study was to demonstrate how profilin1 affected pancreatic cancer radiosensitivity. We showed profilin1 was down-regulated in pancreatic cancer cells after exposure to radiation, and re-expression of profilin1 suppressed tumor cell viability and increased DNA damage following irradiation. Further studies revealed that up-regulation of profilin1 facilitated apoptosis and repressed autophagy induced by irradiation, which might sensitize pancreatic cancer cells to radiation treatment. Our findings may provide a novel therapeutic strategy for sensitizing pancreatic cancer to radiotherapy.
    No preview · Article · Jun 2013 · Current Molecular Medicine
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    ABSTRACT: Upregulation of L-type amino acid transporter 1 (LAT1) has been reported to be associated with a poor prognosis in a variety of malignant tumors. However, the impact of LAT1 in hepatocellular carcinoma (HCC) remains unclear. The objective of this study was to investigate whether the expression of LAT1 in HCC was associated with established clinicopathological features. Quantitative reverse transcription polymerase chain reaction was used to detect LAT1 mRNA expression in 23 pairs of fresh-frozen HCC tissues and corresponding noncancerous tissues. Results showed that LAT1 mRNA expression level in HCC tissues was significantly higher than that in corresponding noncancerous tissues. To investigate the association between LAT1 protein expression and clinicopathological characteristics of HCC, immunohistochemistry was performed in 148 archived paraffin-embedded HCC samples. High LAT1 expression in HCC was associated significantly with tumor size (P = 0.032), histological differentiation (P = 0.003), and tumor stage (P = 0.01). Kaplan-Meier curves demonstrated that patients with a high expression of LAT1 have a significantly increased risk of shortened survival time. Moreover, stepwise Cox regression showed that LAT1 expression may be an independent prognostic factor. Collectively, our study demonstrated that LAT1was overexpressed in HCC and could be served as a potential prognostic marker.
    No preview · Article · May 2013 · Tumor Biology
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    ABSTRACT: c-Met, the receptor for hepatocyte growth factor (HGF), is cell surface tyrosine kinase that controls cancer cell growth, survival, invasion and metastasis. Post-translational modification, such as glycosylation, plays an essential role in regulating the function of cell surface molecules. Whether glycosylation modification regulates the enzymatic properties of c-Met is unknown. In this study, we investigated the effect of glycosylation on the function of c-Met. We found that c-Met is an N-linked glycosylated protein. Both pro-Met and p145Met (the β subunit of mature c-Met) have N-linked glycosylation. Glycosylation inhibitor studies revealed that the N-glycosylation modification of p145Met is from pro-Met, but not due to the further modification of pro-Met. Importantly, blocking the N-glycosylation targets pro-Met to cytoplasm and initiates its phosphorylation independent of HGF engagement. Nonglycosylated pro-Met activates c-Met downstream pathways to a certain extent to compensate for the degradation of p145Met induced by glycosylation blocking-mediated endoplasmic reticulum (ER) stress. J. Cell. Biochem. © 2012 Wiley Periodicals, Inc.
    No preview · Article · Apr 2013 · Journal of Cellular Biochemistry
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    ABSTRACT: To investigate whether the phosphorylation (functionally inhibitive) of eukaryotic initiation factor 2-alpha (eIF2-a) affects the molecular mechanism of cisplatin-induced cellular apoptosis in human hepatocellular carcinoma (HCC). The human HCC cultured cell lines SMMC-7221 and HepG2 were treated with cisplatin alone (controls; 24 h) or in combination with pre-transfection of a dominant-negative eIF2-a mutant (eIF2aS51A) or pre-exposure to an eIF2-a-specific phosphatase inhibitor (salubrinal) to decrease or increase the phosphorylation level, respectively. Changes in expression of apoptosis markers were quantitatively and qualitatively assessed by flow cytometry and western blot analysis. The significance of differences among groups was assessed by analysis of variance testing and of differences between groups was assessed by t-test. Cisplatin treatment induced the appropriate functional-inhibitive phosphorylation of eIF2-a on serine 51. Cisplatin treatment (10 mg/ml) induced significant apoptosis in the eIF2aS51A pre-transfected SMMC-7721 (control: 21.7 +/- 1.5% vs. 50.7 +/- 2.1%, t = 19.454, P less than 0.05) and HepG2 (21.0 +/- 1.0% vs. 57.3 +/- 2.1%, t = 27.250, P less than 0.05). Salubrinal pre-treatment significantly inhibited the cisplatin (15 mg/ml)-induced apoptosis in SMMC-7721 (control: 50.3 +/- 2.5% vs. 16.3 +/- 2.1%, t = 18.031, P less than 0.05) and HepG2 (42.0 +/- 2.6% vs. 12.0 +/- 2.0%, t = 15.667, P less than 0.05). Phosphorylation of eIF2-a may act to inhibit cisplatin-induced apoptosis of HCC.
    No preview · Article · Apr 2013 · Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology
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    ABSTRACT: Androgen receptor (AR) signaling plays an important role in the development and progression of several liver diseases, including hepatocellular carcinoma (HCC) and non-alcoholic fatty liver disease (NAFLD). Dihydrotestosterone (DHT) is the active metabolite of the major circulating androgen, testosterone. In this study, we investigated the effect of DHT on human liver cells. We found that DHT not only induces cell cycle arrest but also initiates apoptosis in androgen-sensitive liver cells, such as SMMC-7721 and L02. Importantly, DHT/AR induces the activation of RNA-dependent protein kinase (PKR)/eukaryotic initiation factor-2 alpha (eIF2α) cascades in androgen-sensitive liver cells. PKR/eIF2α activation-induced growth arrest and DNA damage-inducible gene 153 (GADD153) and heat shock protein 27 (Hsp27) expression contribute to cell cycle arrest in response to DHT. It is notable that DHT administration results in androgen-sensitive liver cells apoptosis, at least in part, through PKR/eIF2α/GADD153 cascades. These results suggest that the androgen/AR pathway plays a pivotal role in liver cell growth and apoptosis regulating, whose deregulation might be involved in the pathogenesis of liver diseases.
    No preview · Article · May 2012 · Journal of Cellular Biochemistry
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    ABSTRACT: To investigate the role of miR-221/222 in inhibiting endoplasmic reticulum stress-induced human hepatocarcinoma cells apoptosis. miR-221/222 mimics and inhibitors were used to mimic or block the function of endogenous miR-221/222 respectively. Western blot and flow cytometry were used to test the effects of miR-221/222 on cell cycle and apoptosis under endoplasmic reticulum stress in human hepatocellular carcinoma cells. Endoplasmic reticulum stress resulted in miR-221/222 down-regulation in human hepatocellular carcinoma cells. miR-221/222 mimics and inhibitors inhibited and promoted respectively endoplasmic reticulum stress-mediated p27Kip1 induction. Moreover, p27Kip1 suppression not only resulted in reduction in the fraction of G1 phase cells, but also promoted the endoplasmic reticulum stress-mediated apoptosis in human hepatocellular carcinoma cells. miR-221/222 were downregulated by endoplasmic reticulum stress in human hepatocellular carcinoma cells, which subsequently protected human hepatocellular carcinoma cells against endoplasmic reticulum stress-induced apoptosis through p27Kip1 regulation.
    No preview · Article · Mar 2011 · Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology
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    ABSTRACT: Cancer cells are relatively resistant to endoplasmic reticulum (ER) stress-induced apoptosis. However, the underlying mechanisms remain largely unclear. We observed that the microRNAs miR-221/222 are associated with apoptosis regulation under ER stress in human hepatocellular carcinoma (HCC) cells. Induction of ER stress does not trigger significant apoptosis but obviously causes downregulation of miR-221/222 in HCC cells. In these cells, ER stress-induced apoptosis is enhanced by miR-221/222 mimics and attenuated by miR-221/222 inhibitors. miR-221/222 promoted-apoptosis under ER stress is associated with p27(Kip1)- and MEK/ERK-mediated cell cycle regulation. Our results suggest that suppression of miR-221/222 plays a crucial role in the protection against apoptosis induced by ER stress in HCC cells.
    No preview · Article · Jul 2010 · Biological Chemistry

Publication Stats

72 Citations
34.16 Total Impact Points

Institutions

  • 2013-2014
    • Second Military Medical University, Shanghai
      Shanghai, Shanghai Shi, China
    • Luzhou Medical College
      Lu-chou, Sichuan, China
    • Changhai Hospital, Shanghai
      Shanghai, Shanghai Shi, China