Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer

AbstractNicotine addiction and the occurrence of lymph node spread are two major significant factors associated with esophageal cancer’s poor prognosis; however, nicotine’s role in inducing lymphatic metastasis of esophageal cancer remains unclear. Here we show that OTU domain-containing protein 3 (OTUD3) is downregulated by nicotine and correlates with poor prognosis in heavy-smoking esophageal cancer patients. OTUD3 directly interacts with ZFP36 ring finger protein (ZFP36) and stabilizes it by inhibiting FBXW7-mediated K48-linked polyubiquitination. ZFP36 binds with the VEGF-C 3-‘UTR and recruits the RNA degrading complex to induce its rapid mRNA decay. Downregulation of OTUD3 and ZFP36 is essential for nicotine-induced VEGF-C production and lymphatic metastasis in esophageal cancer. This study establishes that the OTUD3/ZFP36/VEGF-C axis plays a vital role in nicotine addiction-induced lymphatic metastasis, suggesting that OTUD3 may serve as a prognostic marker, and induction of the VEGF-C mRNA decay might be a potential therapeutic strategy against human esophageal cancer.

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Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer

10.21203/rs.3.rs-379260/v1 ◽

2021 ◽

Author(s):

Libing Song ◽

Meng Wang ◽

Yue Li ◽

Yunyun Xiao ◽

Muwen Yang ◽

...

Keyword(s):

Esophageal Cancer ◽

Lymphatic Metastasis ◽

Poor Prognosis ◽

Mrna Decay ◽

Ring Finger ◽

Nicotine Addiction ◽

Vital Role ◽

Heavy Smoking ◽

Human Esophageal Cancer ◽

Significant Factors

Abstract Nicotine addiction and the occurrence of lymph node spread are two major significant factors associated with esophageal cancer's poor prognosis; however, nicotine's role in inducing lymphatic metastasis of esophageal cancer remains unclear. Here we showed that OTU domain-containing protein 3 (OTUD3) was downregulated by nicotine and correlated with poor prognosis in heavy-smoking esophageal cancer patients. Nicotine-mediated OTUD3 downregulation promoted lymphatic metastasis by inducing substantial tumor-induced lymphangiogenesis. At the mechanistic level, OTUD3 directly interacted with ZFP36 ring finger protein (ZFP36) and stabilized it by inhibiting FBXW7-mediated K48-linked polyubiquitination. ZFP36 bound with the VEGF-C 3-'UTR and recruited the RNA degrading complex to induce its rapid mRNA decay. Thus, downregulation of OTUD3 and ZFP36 was essential for nicotine-induced VEGF-C production and lymphatic metastasis in esophageal cancer. This study establishes that the OTUD3/ZFP36/VEGF-C axis plays a vital role in nicotine addiction-induced lymphatic metastasis. It also suggests that OTUD3 may serve as a prognostic marker, and induction of the VEGF-C mRNA decay might be a potential therapeutic strategy against human esophageal cancer.

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Blockade of TRIM59 to enhance chemosensitivity of esophageal cancer cell to cisplatin by upregulating p53 expression.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16509 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16509-e16509

Author(s):

Rong Feng Liu ◽

Jian Shi ◽

Xiaoyang Duan

Keyword(s):

Esophageal Cancer ◽

P53 Protein ◽

Ring Finger ◽

Poor Survival ◽

Ring Finger Domain ◽

P53 Expression ◽

Chemotherapy Sensitivity ◽

Esophageal Cancer Cell ◽

Proliferation And Metastasis ◽

Human Esophageal Cancer

e16509 Background: TRIM59 is the one of TRIM family characterized by an N-terminal really interesting new gene (RING)-finger domain, followed by two zinc-finger domains named B2 box and a coiled-coil (CC). Ubiquitination plays a vital role in the degradation of many kinds of proteins that function in the intracellular signaling pathway, cell cycle, DNA repair and transcriptional regulation. Because of the RING-finger domain, TRIM59 protein functions as E3 ubiquitin ligase activity and can selectively target ubiquitin-modified proteins for proteasomes or degradation. In additional, accumulating finding results have shown the TRIM proteins promote positively or negatively carcinogenesis. Here we focus on the TRIM59 protein: oncogenic activity in the promoting proliferation and metastasis of esophageal cancer cell. Methods: None. Results: Human esophageal cancer cells’ motility adopts various modes resulting in the HESC progression and poor survival of patients. We proved that TRIM59 is aberrantly up-regulated in metastatic human esophageal cancer (hESC) than adjacent normal esophageal tissue, which is on behalf of poor survival and advanced TNM state among the hESC patients. At the molecular level, we proved TRIM59 as an E3 putative ubiquitin ligase targets the p53 protein leading to the increased degradation of p53 resulting in the less chemotherapy sensitivity to cisplatin. TRIM59 knockdown in hESC cell lines reduced TRIM59 expression and promotes p53 protein level and decreased the proliferation, clone formation, migration. At the same time, hESC cell lines showed more sensitive to the cisplatin in the cell line treated with knockdown of TRIM59. These findings establish the relationship between TRIM59 and p53 and chemotherapy sensitivity of cisplatin and TRIM59 may be a promising prognostic indicator for esophageal squamous cell carcinoma (ESCA) patients. Conclusions: We have confirmed that the up-regulation of TRIM59 in human esophageal cancer tissues closely correlates with poor prognosis of patients and TRIM59 serves as an oncogene promoting the proliferation and metastasis of esophageal cancer. The study demonstrates that knockdown of TRIM59 inhibited the growth and invasion of Eca109 cancer cells and strengthened the chemosensitivity to cisplatin through the mechanism of increasing the p53 expression. These results suggest that combination of TRIM59 knockdown with cisplatin might provide a promising strategy to treat the patients with esophageal cancer.

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Correlation of hypoxia inducible factor-1α with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer

Experimental and Molecular Pathology ◽

10.1016/j.yexmp.2004.11.002 ◽

2005 ◽

Vol 78 (2) ◽

pp. 123-130 ◽

Cited By ~ 61

Author(s):

Miwako Katsuta ◽

Masao Miyashita ◽

Hiroshi Makino ◽

Tsutomu Nomura ◽

Seiichi Shinji ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Esophageal Cancer ◽

Growth Factor ◽

Lymphatic Metastasis ◽

Hypoxia Inducible Factor ◽

Vascular Endothelial ◽

Hypoxia Inducible Factor 1Α ◽

Human Esophageal Cancer ◽

Factor C ◽

Endothelial Growth Factor

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Methylation of ZNF331 Promotes Cell Invasion and Migration in Human Esophageal Cancer

Current Protein and Peptide Science ◽

10.2174/138920371604150429155255 ◽

2015 ◽

Vol 16 (4) ◽

pp. 322-328 ◽

Cited By ~ 10

Author(s):

Suzhen Jiang ◽

Enqiang Linghu ◽

Qimin Zhan ◽

Weidong Han ◽

Mingzhou Guo

Keyword(s):

Esophageal Cancer ◽

Cell Invasion ◽

Invasion And Migration ◽

And Migration ◽

Human Esophageal Cancer

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Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

Scientific Reports ◽

10.1038/s41598-021-81465-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ryoichi Katsube ◽

Kazuhiro Noma ◽

Toshiaki Ohara ◽

Noriyuki Nishiwaki ◽

Teruki Kobayashi ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Near Infrared ◽

Fibroblast Activation Protein ◽

Therapeutic Resistance ◽

Fibroblast Activation ◽

Human Esophageal Cancer

AbstractCancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

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Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-15-2254 ◽

2016 ◽

Vol 22 (16) ◽

pp. 4145-4157 ◽

Cited By ~ 45

Author(s):

Ping Chen ◽

Tao Hu ◽

Yupei Liang ◽

Pei Li ◽

Xiaoyu Chen ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Cells ◽

Apoptosis Pathway ◽

Extrinsic Apoptosis ◽

Human Esophageal Cancer ◽

Esophageal Cancer Cells

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Characteristics of P-Type and N-Type Photoelectrochemical Biosensors: A Case Study for Esophageal Cancer Detection

Nanomaterials ◽

10.3390/nano11051065 ◽

2021 ◽

Vol 11 (5) ◽

pp. 1065

Author(s):

Joseph-Hang Leung ◽

Hong-Thai Nguyen ◽

Shih-Wei Feng ◽

Sofya B. Artemkina ◽

Vladimir E. Fedorov ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Cells ◽

Carrier Transport ◽

X Ray Diffraction ◽

Photoelectrochemical Response ◽

Carrier Separation ◽

Human Esophageal Cancer ◽

P Type ◽

Esophageal Cancer Cells

P-type and N-type photoelectrochemical (PEC) biosensors were established in the laboratory to discuss the correlation between characteristic substances and photoactive material properties through the photogenerated charge carrier transport mechanism. Four types of human esophageal cancer cells (ECCs) were analyzed without requiring additional bias voltage. Photoelectrical characteristics were examined by scanning electron microscopy (SEM), X-ray diffraction (XRD), UV–vis reflectance spectroscopy, and photocurrent response analyses. Results showed that smaller photocurrent was measured in cases with advanced cancer stages. Glutathione (L-glutathione reduced, GSH) and Glutathione disulfide (GSSG) in cancer cells carry out redox reactions during carrier separation, which changes the photocurrent. The sensor can identify ECC stages with a certain level of photoelectrochemical response. The detection error can be optimized by adjusting the number of cells, and the detection time of about 5 min allowed repeated measurement.

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