HPV16 E6/E7 upregulates HIF-2α and VEGF by inhibiting LKB1 in lung cancer cells
Long-term persistent infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. However, molecular mechanisms of HPV16 E6/E7 induction of lung cancer are not fully understood. Using bi-directional genetic manipulation and four well-established lung...
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2017-07-01
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| Series: | Tumor Biology |
| Online Access: | https://doi.org/10.1177/1010428317717137 |
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| _version_ | 1849709789294100480 |
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| author | Jian-Shuang Shao Jian Sun Shiyu Wang Katherine Chung Jin Tong Du Jason Wang Xue-Shan Qiu En-Hua Wang Guang-Ping Wu |
| author_facet | Jian-Shuang Shao Jian Sun Shiyu Wang Katherine Chung Jin Tong Du Jason Wang Xue-Shan Qiu En-Hua Wang Guang-Ping Wu |
| author_sort | Jian-Shuang Shao |
| collection | DOAJ |
| description | Long-term persistent infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. However, molecular mechanisms of HPV16 E6/E7 induction of lung cancer are not fully understood. Using bi-directional genetic manipulation and four well-established lung cancer cell lines, we showed HPV16 E6/E7 downregulated expression of liver kinase B1 at both protein and messenger RNA levels; liver kinase B1 downregulated hypoxia-inducible factor 2α at protein level but not at messenger RNA level, and hypoxia-inducible factor 2α upregulated vascular endothelial growth factor at both protein and messenger RNA levels. This is the first study to show hypoxia-inducible factor 2α as a downstream effector of liver kinase B1 in lung cancer cells. Our results indicate that HPV16 E6/E7 indirectly upregulated the expression of vascular endothelial growth factor by inhibition of liver kinase B1 expression and upregulation of hypoxia-inducible factor 2α expression, thus propose a human papillomavirus–liver kinase B1–hypoxia-inducible factor 2α–vascular endothelial growth factor axis for the tumorigenesis of lung cancer. Our study also provides new evidence to support the critical role of liver kinase B1 in the pathogenesis of human papillomavirus–related lung cancer and suggests novel therapeutic targets. |
| format | Article |
| id | doaj-art-2e1077f04bb240d68893ed641ddf2694 |
| institution | DOAJ |
| issn | 1423-0380 |
| language | English |
| publishDate | 2017-07-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Tumor Biology |
| spelling | doaj-art-2e1077f04bb240d68893ed641ddf26942025-08-20T03:15:09ZengSAGE PublishingTumor Biology1423-03802017-07-013910.1177/1010428317717137HPV16 E6/E7 upregulates HIF-2α and VEGF by inhibiting LKB1 in lung cancer cellsJian-Shuang Shao0Jian Sun1Shiyu Wang2Katherine Chung3Jin Tong Du4Jason Wang5Xue-Shan Qiu6En-Hua Wang7Guang-Ping Wu8Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, ChinaDepartment of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, ChinaGeisinger Commonwealth School of Medicine, Scranton, PA, USAGeisinger Commonwealth School of Medicine, Scranton, PA, USADepartment of Physiology and Pharmacology, Schulich Medicine & Dentistry, Western University, London, ON, CanadaCollege of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI, USADepartment of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, ChinaDepartment of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, ChinaDepartment of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, ChinaLong-term persistent infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. However, molecular mechanisms of HPV16 E6/E7 induction of lung cancer are not fully understood. Using bi-directional genetic manipulation and four well-established lung cancer cell lines, we showed HPV16 E6/E7 downregulated expression of liver kinase B1 at both protein and messenger RNA levels; liver kinase B1 downregulated hypoxia-inducible factor 2α at protein level but not at messenger RNA level, and hypoxia-inducible factor 2α upregulated vascular endothelial growth factor at both protein and messenger RNA levels. This is the first study to show hypoxia-inducible factor 2α as a downstream effector of liver kinase B1 in lung cancer cells. Our results indicate that HPV16 E6/E7 indirectly upregulated the expression of vascular endothelial growth factor by inhibition of liver kinase B1 expression and upregulation of hypoxia-inducible factor 2α expression, thus propose a human papillomavirus–liver kinase B1–hypoxia-inducible factor 2α–vascular endothelial growth factor axis for the tumorigenesis of lung cancer. Our study also provides new evidence to support the critical role of liver kinase B1 in the pathogenesis of human papillomavirus–related lung cancer and suggests novel therapeutic targets.https://doi.org/10.1177/1010428317717137 |
| spellingShingle | Jian-Shuang Shao Jian Sun Shiyu Wang Katherine Chung Jin Tong Du Jason Wang Xue-Shan Qiu En-Hua Wang Guang-Ping Wu HPV16 E6/E7 upregulates HIF-2α and VEGF by inhibiting LKB1 in lung cancer cells Tumor Biology |
| title | HPV16 E6/E7 upregulates HIF-2α and VEGF by inhibiting LKB1 in lung cancer cells |
| title_full | HPV16 E6/E7 upregulates HIF-2α and VEGF by inhibiting LKB1 in lung cancer cells |
| title_fullStr | HPV16 E6/E7 upregulates HIF-2α and VEGF by inhibiting LKB1 in lung cancer cells |
| title_full_unstemmed | HPV16 E6/E7 upregulates HIF-2α and VEGF by inhibiting LKB1 in lung cancer cells |
| title_short | HPV16 E6/E7 upregulates HIF-2α and VEGF by inhibiting LKB1 in lung cancer cells |
| title_sort | hpv16 e6 e7 upregulates hif 2α and vegf by inhibiting lkb1 in lung cancer cells |
| url | https://doi.org/10.1177/1010428317717137 |
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