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Gastrointestinal cancer
A Hypoxia-Induced SCFFBXL1 E3 Ligase Ubiquitinates and Degrades the MEN1 Tumor Suppressor to Promote Colorectal Cancer Tumorigenesis
Jun Zeng, Xiao-qing Xiao, Zhi-yong Zhou
Cancer Res Treat. 2022;54(2):525-540.   Published online June 29, 2021
DOI: https://doi.org/10.4143/crt.2021.373
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Emerging evidence has shown that SKP1-cullin-1-F-box-protein (SCF) E3 ligases contribute to the pathogenesis of different cancers by mediating the ubiquitination and degradation of tumor suppressors. However, the functions of SCF E3 ligases in the pathogenesis of colorectal cancer (CRC) remain obscure.
Materials and Methods
The cancerous and adjacent noncancerous tissues from CRC patients were collected, and protein levels were analyzed. Lentiviral short hairpin RNA (shRNA) and plasmid transfection were used to knock down and overexpress gene expression in CRC cell lines. Immunoprecipitation (IP), mass spectrometry, and co-IP analyses were used to determine protein interactions and the assembly of the SCF complex. Cell proliferation, migration, and tumor xenograft assays were performed to examine the effects of SCF members on CRC cell growth in vitro and in vivo.
Results
Hypoxia activated the docking of hypoxia-inducible factor 1α (HIF1α) onto the CUL1 promoter and induced CUL1 expression in CRC cells. CUL1 coupled with RBX1, SKP1, and FBXL1 to assemble the SCFFBXL1 complex in CRC biopsies and cells. The SCFFBXL1 E3 ligase specifically ubiquitinated and degraded the MEN1 tumor suppressor. Knockdown of HIF1α or SCFFBXL1 members, or blockage of SCFFBXL1 by two inhibitors (DT204 and SZLP1-41) caused the accumulation of MEN1 protein and led to a significant decrease in cell proliferation and migration in vitro and tumor growth in vivo.
Conclusion
The SCFFBXL1 E3 ligase is required for the ubiquitination of MEN1, and disruption of this complex may represent a new therapeutic strategy for the treatment of CRC.

Citations

Citations to this article as recorded by  
  • Role of protein degradation systems in colorectal cancer
    Zihan Cui, Mingqi Cong, Shengjie Yin, Yuqi Li, Yuguang Ye, Xi Liu, Jing Tang
    Cell Death Discovery.2024;[Epub]     CrossRef
  • Spatially resolved transcriptomics revealed local invasion-related genes in colorectal cancer
    Hong-Tao Liu, Si-Yuan Chen, Ling-Long Peng, Li Zhong, Li Zhou, Si-Qi Liao, Zhi-Ji Chen, Qing-Liang Wang, Song He, Zhi-Hang Zhou
    Frontiers in Oncology.2023;[Epub]     CrossRef
  • Estrogen-dependent activation of NCOA3 couples with p300 and NF-κB to mediate antiapoptotic genes in ER-positive breast cancer cells
    Jun Wang, Zhiyong Zhou
    Discover Oncology.2023;[Epub]     CrossRef
  • Rational targeting of autophagy in colorectal cancer therapy: From molecular interactions to pharmacological compounds
    Canhui Jin, Tianbao Wang, Yanhui Yang, Pin Zhou, Juncheng Li, Wenhao Wu, Xin Lv, Guoqing Ma, Aihong Wang
    Environmental Research.2023; 227: 115721.     CrossRef
  • 6,644 View
  • 145 Download
  • 4 Web of Science
  • 4 Crossref
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Targeting Hypoxia Using Evofosfamide and Companion Hypoxia Imaging of FMISO-PET in Advanced Biliary Tract Cancer
Jeesun Yoon, Seo Young Kang, Kyung-Hun Lee, Gi Jeong Cheon, Do-Youn Oh
Cancer Res Treat. 2021;53(2):471-479.   Published online October 22, 2020
DOI: https://doi.org/10.4143/crt.2020.577
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Hypoxia is widely known as one of the mechanisms of chemoresistance and as an environmental condition which triggers invasion and metastasis of cancer. Evofosfamide is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard conjugated with 2-nitroimidazole. Biliary tract cancer (BTC) is known to contain large hypoxic area. This study evaluated the efficacy and safety of evofosfamide as a second-line treatment of advanced BTC.
Materials and Methods
Patients received evofosfamide at a dose of 340 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Primary end-point was progression-free survival (PFS) rate at 4-months (4m-PFSR). Secondary end-points included overall survival (OS), PFS, disease control rate (DCR), metabolic response by 18F-fluorodeoxyglucose positron emission tomography (PET), hypoxic parameters evaluated by 18F-fluoromisonidazole (FMISO) PET and toxicity.
Results
Twenty patients were treated with evofosfamide, with 16 response-evaluable patients. There was no objective response; stable disease was observed in nine patients, with a DCR of 56.25%. 4m-PFSR was 40.6%. Median PFS was 3.60 months (95% confidence interval [CI], 1.68 to 5.52). Median OS was 6.37 months (95% CI, 3.94 to 8.79). Reduction of tumor metabolic activity was observed in eight of 15 patients (53.3%). High baseline hypoxic parameters were associated with poor PFS. Change of hypoxic parameters between pretreatment and post-treatment reflected hypoxic-activated drug response. There was no treatment-related death.
Conclusion
Evofosfamide as second-line treatment of advanced BTC showed acceptable safety and comparable efficacy to other agents. Changes in volumetric parameters measured with FMISO PET, showing the degree of tumor hypoxia, reflected the response to evofosfamide based on the mode of action.

Citations

Citations to this article as recorded by  
  • Functional Imaging of Hypoxia: PET and MRI
    Ryan C. Perez, DaeHee Kim, Aaron W. P. Maxwell, Juan C. Camacho
    Cancers.2023; 15(13): 3336.     CrossRef
  • Phase Ib dose-escalation study of the hypoxia-modifier Myo-inositol trispyrophosphate in patients with hepatopancreatobiliary tumors
    Marcel A. Schneider, Michael Linecker, Ralph Fritsch, Urs J. Muehlematter, Daniel Stocker, Bernhard Pestalozzi, Panagiotis Samaras, Alexander Jetter, Philipp Kron, Henrik Petrowsky, Claude Nicolau, Jean-Marie Lehn, Bostjan Humar, Rolf Graf, Pierre-Alain C
    Nature Communications.2021;[Epub]     CrossRef
  • 5,803 View
  • 181 Download
  • 2 Web of Science
  • 2 Crossref
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Glucose Transporter-1 Expression in Squamous Cell Carcinoma of the Tongue
Yoon Seok Choi, Seok Jin Kim, Dae Sik Kim, Seh Jong Park, Yong Park, Hye Jin Shin, Kwang-Yoon Jung, Seung-Kuk Baek, Bong Kyung Shin, Jung Woo Choi, Byung Soo Kim, Sang Won Shin, Yeul Hong Kim, Jun Suk Kim
Cancer Res Treat. 2007;39(3):109-115.   Published online September 30, 2007
DOI: https://doi.org/10.4143/crt.2007.39.3.109
AbstractAbstract PDFPubReaderePub
Purpose

Tumor cells are known to express hypoxia-related proteins such as glucose transporter-1 (Glut-1). These hypoxia-induced changes may allow tumor cells to survive under sustained hypoxic microenvironments, and the surviving tumor cell under hypoxia may develop a more aggressive phenotype and so result in a poor prognosis.

Materials and Methods

The Glut-1 expression was analyzed by immunohistochemistry, and its association with the prognosis was assessed in 60 patients with squamous cell carcinoma of the tongue.

Results

The Glut-1 expression was diffuse with a membranous pattern, and the median percentage of Glut-1 positive tumor cells was 60% (range: 0.0~90.0%). A high Glut-1 expression (the percentage of positive tumor cells ≥ the median value, 60%) was associated with the location of primary lesion, lymph node metastasis status and disease stage (p<0.05). The expression of Glut-1 was correlated with the Ki-67 expression (r=0.406, p=0.001). Microvessel density, as represented by CD31 staining, was also correlated with the Glut-1 expression although its significance is weak (r=0.267, p=0.039). On the univariate analysis, the group with a high Glut-1 expression showed poorer overall survival than the group with a low Glut-1 expression (p<0.05). However, the Glut-1 expression failed to show any independent prognostic significance on the multivariate analysis.

Conclusion

The expression of Glut-1 may be useful for predicting the prognosis and determining the treatment strategy for the management of squamous cell carcinoma of the tongue.

Citations

Citations to this article as recorded by  
  • Study of expression of GLUT-1 in oral potentially malignant disorders and oral squamous cell carcinoma: An immuno-histochemical analysis
    Shylaja K. Attur, Anil Patel, Kailash M. Attur
    Journal of Oral and Maxillofacial Pathology.2024; 28(1): 70.     CrossRef
  • Prognostic value of glycolysis markers in head and neck squamous cell carcinoma: a meta-analysis
    Yanting Wang, Yuanyuan Li, Laibo Jiang, Xianyue Ren, Bin Cheng, Juan Xia
    Aging.2021; 13(5): 7284.     CrossRef
  • The Role of Glucose Transporters in Oral Squamous Cell Carcinoma
    Heinrich Botha, Camile S. Farah, Kendrick Koo, Nicola Cirillo, Michael McCullough, Rita Paolini, Antonio Celentano
    Biomolecules.2021; 11(8): 1070.     CrossRef
  • Glut 1 in Cancer Cells and the Inhibitory Action of Resveratrol as A Potential Therapeutic Strategy
    Angara Zambrano, Matías Molt, Elena Uribe, Mónica Salas
    International Journal of Molecular Sciences.2019; 20(13): 3374.     CrossRef
  • Can increased metabolic status be a grading tool for oral squamous cell carcinoma? A glucose transporter 1 immunoexpression study
    Abikshyeet Panda, Alokenath Bandyopadhyay, Gouse Mohiddin, Malvika Raghuvanshi, SanjayKumar Sahoo, Lipsa Bhuyan
    Nigerian Journal of Surgery.2019; 25(2): 203.     CrossRef
  • Plumbagin‐mediating GLUT1 suppresses the growth of human tongue squamous cell carcinoma
    S Na, J Zhang, X Zhou, A Tang, D Huang, Q Xu, D Xue, J Qiu
    Oral Diseases.2018; 24(6): 920.     CrossRef
  • Expression of GLUT-1 in oral squamous cell carcinoma in tobacco and non-tobacco users
    Neha Azad, Malti Kumari Maurya, Meenakshi Kar, Madhu Mati Goel, Ajay Kumar Singh, Mala Sagar, Divya Mehrotra, Vijay Kumar
    Journal of Oral Biology and Craniofacial Research.2016; 6(1): 25.     CrossRef
  • Distribution of Hypoxia-Inducible Factor-1α and Glucose Transporter-1 in Human Tongue Cancers
    Marcelo Gadelha Vasconcelos, Rodrigo Gadelha Vasconcelos, Denise Hélen Imaculada Pereira de Oliveira, Edilmar de Moura Santos, Leão Pereira Pinto, Éricka Janine Dantas da Silveira, Lélia Maria Guedes Queiroz
    Journal of Oral and Maxillofacial Surgery.2015; 73(9): 1753.     CrossRef
  • Expression of glucose transporters in cancers
    Leszek Szablewski
    Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.2013; 1835(2): 164.     CrossRef
  • T-Type Ca2+Channels in Normal and Abnormal Brain Functions
    Eunji Cheong, Hee-Sup Shin
    Physiological Reviews.2013; 93(3): 961.     CrossRef
  • Glucose uptake mediated by glucose transporter 1 is essential for early tooth morphogenesis and size determination of murine molars
    Hiroko Ida-Yonemochi, Mitsushiro Nakatomi, Hidemitsu Harada, Hiroki Takata, Otto Baba, Hayato Ohshima
    Developmental Biology.2012; 363(1): 52.     CrossRef
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    Ja Seung Koo, Haeryoung Kim
    Tumor Biology.2011; 32(5): 893.     CrossRef
  • 10,622 View
  • 57 Download
  • 12 Crossref
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Studies on the Mechanism of Hypoxic Increase of VEGF Expression in the Hep3B Human Hepatoma Cells
Yoo Wook Kwon, Soo Kyung Bae, Jung Ae Kim, Kyu Won Kim, Byung Chae Park
J Korean Cancer Assoc. 1997;29(2):220-226.
AbstractAbstract PDF
PURPOSE
Hepatocellular carcinoma (HCC), a typical hypervasculized tumor is very sensitive to hypoxia and vascular endothelial growth factor (VEGF) has previously been identified to be up-regulated in response to hypoxia in several cell types. However, the molecular mechanisms by which hypoxia is sensed by the cells remain enigmatic. To investigate whether calcium and AP-1 are involved in hypoxia-sensing mechanism, we performed following experiments.
MATERIALS AND METHODS
Hep3B cells were grown in hypoxic condition. To assess cell viability, MTT assay was performed. To investigate the effect of calcium and AP-1, northern blot analysis was performed after treatment with BAPTA/AM.
RESULTS
The expression of VEGF was significantly up-regulated by hypoxia in Hep3B, hepatocellular carcinoma cell line. The increased expression of VEGF induced by hypoxia was blocked by the addition of BAPTA/AM, a cytosolic calcium chelator to the media. In addition, we found that the expression of c-jun protooncogene was also up-regulated by hypoxia. Hypoxic increase of c-jun expression was also normalized by the treatment with BAPTA/AM.
CONCLUSION
These results suggest that the increased expression of VEGF by hypoxia is mediated through the calcium and c-jun signalling pathway in the Hep3B human hepatoma cell lines.
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  • 15 Download
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