Lysyl oxidase-like 2 promotes stemness and enhances antitumor effects of gefitinib in head and neck cancer via IFIT1 and IFIT3
Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has recently been identified as an important regulator of tumor progression and metastasis. This study discovered that LOXL2 expression in oral squamous cell carcinoma (OSCC) tissues was significantly associated with tumor clinical stag...
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| Veröffentlicht in: | Cancer science 2023-10, Vol.114 (10), p.3957-3971 |
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| creator | Lu, Yi-Jie Deng, Yi-Ting Ko, Hui-Hsin Peng, Hsin-Hui Lee, Hsiang-Chieh Kuo, Mark Yen-Ping Cheng, Shih-Jung |
| description | Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has recently been identified as an important regulator of tumor progression and metastasis. This study discovered that LOXL2 expression in oral squamous cell carcinoma (OSCC) tissues was significantly associated with tumor clinical stage, lymph node metastasis and patients' overall survival time. LOXL2-overexpressing human buccal SCC TW2.6 (TW2.6/LOXL2) and hypopharyngeal SCC FaDu (FaDu/LOXL2) cells exhibited enhanced migration, invasion, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) phenotypes, independently of its enzymatic activity. Moreover, TW2.6/LOXL2 significantly increased tumor-initiating frequency in SCID mice. We further demonstrated that LOXL2 increased the levels of interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and IFIT3 in TW2.6/LOXL2 and FaDu/LOXL2 cells. We also identified IFIT1 and IFIT3 as key downstream components of LOXL2 action in migration, invasion, EMT, and CSC phenotypes in TW2.6 and FaDu cells. Furthermore, a significant positive correlation between LOXL2 expression and IFIT1 and IFIT3 overexpression in human OSCC tissues was observed. In addition, TW2.6/LOXL2 and FaDu/LOXL2 cells were 3.3- to 3.6-fold more susceptible to the epidermal growth factor receptor (EGFR) inhibitor gefitinib than were their respective control cells. The antitumor effect of gefitinib on orthotopic TW2.6/LOXL2 xenograft tumor was fourfold higher than that on controls. Our results indicate that LOXL2 expression is a strong prognostic factor for OSCC and may be used as a marker to identify patients most likely to respond to EGFR-targeted therapy. |
| doi_str_mv | 10.1111/cas.15912 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10551584</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2843037178</sourcerecordid><originalsourceid>FETCH-LOGICAL-c428t-99e5b83c0f500bf82a369bf6510577c64a6dbb408aa85ee63e8e3bb36cba33453</originalsourceid><addsrcrecordid>eNpdkU1v1DAQhiMEoqVw4A8gS1zgkOLPxDkhVFFYaSUu5WzZzrjrNrEX26nYC78dZ1sqYC4z1jzzzlhv07wm-JzU-GB1PidiIPRJc0oYH9oe4-7pse7bATN60rzI-QZj1vGBP29OWM-Hjkp52vzaHvJhQvGnH3WGdvK3gCjapzjHAhnlAnOAnJEOI4Kw08HC-ii-LHNMCJwDWzKKDl2D88UHb5APaAd6PM4EsLfIrmMJ3XmNNpebK3LsrBV72Txzesrw6iGfNd8vP19dfG23375sLj5tW8upLO0wgDCSWewExsZJqlk3GNcJgkXf247rbjSGY6m1FAAdAwnMGNZZoxnjgp01H-9194uZYbQQStKT2ic_63RQUXv1byf4nbqOd6ouEERIXhXePSik-GOBXNTss4Vp0gHikhWtDGY96WVF3_6H3sQlhfq_SvVUcCrEKvj-nrIp5pzAPV5DsFptVdVWdbS1sm_-Pv-R_OMj-w14-Z3-</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2872542554</pqid></control><display><type>article</type><title>Lysyl oxidase-like 2 promotes stemness and enhances antitumor effects of gefitinib in head and neck cancer via IFIT1 and IFIT3</title><source>Wiley-Blackwell Open Access Titles</source><source>DOAJ Directory of Open Access Journals</source><source>Wiley Online Library Journals Frontfile Complete</source><source>PubMed Central</source><creator>Lu, Yi-Jie ; Deng, Yi-Ting ; Ko, Hui-Hsin ; Peng, Hsin-Hui ; Lee, Hsiang-Chieh ; Kuo, Mark Yen-Ping ; Cheng, Shih-Jung</creator><creatorcontrib>Lu, Yi-Jie ; Deng, Yi-Ting ; Ko, Hui-Hsin ; Peng, Hsin-Hui ; Lee, Hsiang-Chieh ; Kuo, Mark Yen-Ping ; Cheng, Shih-Jung</creatorcontrib><description>Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has recently been identified as an important regulator of tumor progression and metastasis. This study discovered that LOXL2 expression in oral squamous cell carcinoma (OSCC) tissues was significantly associated with tumor clinical stage, lymph node metastasis and patients' overall survival time. LOXL2-overexpressing human buccal SCC TW2.6 (TW2.6/LOXL2) and hypopharyngeal SCC FaDu (FaDu/LOXL2) cells exhibited enhanced migration, invasion, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) phenotypes, independently of its enzymatic activity. Moreover, TW2.6/LOXL2 significantly increased tumor-initiating frequency in SCID mice. We further demonstrated that LOXL2 increased the levels of interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and IFIT3 in TW2.6/LOXL2 and FaDu/LOXL2 cells. We also identified IFIT1 and IFIT3 as key downstream components of LOXL2 action in migration, invasion, EMT, and CSC phenotypes in TW2.6 and FaDu cells. Furthermore, a significant positive correlation between LOXL2 expression and IFIT1 and IFIT3 overexpression in human OSCC tissues was observed. In addition, TW2.6/LOXL2 and FaDu/LOXL2 cells were 3.3- to 3.6-fold more susceptible to the epidermal growth factor receptor (EGFR) inhibitor gefitinib than were their respective control cells. The antitumor effect of gefitinib on orthotopic TW2.6/LOXL2 xenograft tumor was fourfold higher than that on controls. Our results indicate that LOXL2 expression is a strong prognostic factor for OSCC and may be used as a marker to identify patients most likely to respond to EGFR-targeted therapy.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.15912</identifier><identifier>PMID: 37496288</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Antitumor activity ; Cancer ; Cell migration ; Clinical outcomes ; Enzymatic activity ; Epidermal growth factor receptors ; Extracellular matrix ; Gefitinib ; Head & neck cancer ; Interferon ; Labeling ; Lymph nodes ; Lymphatic system ; Lysyl oxidase ; Medical prognosis ; Metastases ; Metastasis ; Oral carcinoma ; Oral squamous cell carcinoma ; Original ; ORIGINAL ARTICLES ; Phenotypes ; Plasmids ; Polyclonal antibodies ; Proteins ; Survival analysis ; Tumors</subject><ispartof>Cancer science, 2023-10, Vol.114 (10), p.3957-3971</ispartof><rights>2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2023. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-99e5b83c0f500bf82a369bf6510577c64a6dbb408aa85ee63e8e3bb36cba33453</citedby><cites>FETCH-LOGICAL-c428t-99e5b83c0f500bf82a369bf6510577c64a6dbb408aa85ee63e8e3bb36cba33453</cites><orcidid>0000-0002-2976-6195 ; 0000-0001-8321-2575 ; 0000-0002-3247-2585 ; 0000-0003-4674-4892</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10551584/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10551584/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37496288$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lu, Yi-Jie</creatorcontrib><creatorcontrib>Deng, Yi-Ting</creatorcontrib><creatorcontrib>Ko, Hui-Hsin</creatorcontrib><creatorcontrib>Peng, Hsin-Hui</creatorcontrib><creatorcontrib>Lee, Hsiang-Chieh</creatorcontrib><creatorcontrib>Kuo, Mark Yen-Ping</creatorcontrib><creatorcontrib>Cheng, Shih-Jung</creatorcontrib><title>Lysyl oxidase-like 2 promotes stemness and enhances antitumor effects of gefitinib in head and neck cancer via IFIT1 and IFIT3</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has recently been identified as an important regulator of tumor progression and metastasis. This study discovered that LOXL2 expression in oral squamous cell carcinoma (OSCC) tissues was significantly associated with tumor clinical stage, lymph node metastasis and patients' overall survival time. LOXL2-overexpressing human buccal SCC TW2.6 (TW2.6/LOXL2) and hypopharyngeal SCC FaDu (FaDu/LOXL2) cells exhibited enhanced migration, invasion, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) phenotypes, independently of its enzymatic activity. Moreover, TW2.6/LOXL2 significantly increased tumor-initiating frequency in SCID mice. We further demonstrated that LOXL2 increased the levels of interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and IFIT3 in TW2.6/LOXL2 and FaDu/LOXL2 cells. We also identified IFIT1 and IFIT3 as key downstream components of LOXL2 action in migration, invasion, EMT, and CSC phenotypes in TW2.6 and FaDu cells. Furthermore, a significant positive correlation between LOXL2 expression and IFIT1 and IFIT3 overexpression in human OSCC tissues was observed. In addition, TW2.6/LOXL2 and FaDu/LOXL2 cells were 3.3- to 3.6-fold more susceptible to the epidermal growth factor receptor (EGFR) inhibitor gefitinib than were their respective control cells. The antitumor effect of gefitinib on orthotopic TW2.6/LOXL2 xenograft tumor was fourfold higher than that on controls. 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This study discovered that LOXL2 expression in oral squamous cell carcinoma (OSCC) tissues was significantly associated with tumor clinical stage, lymph node metastasis and patients' overall survival time. LOXL2-overexpressing human buccal SCC TW2.6 (TW2.6/LOXL2) and hypopharyngeal SCC FaDu (FaDu/LOXL2) cells exhibited enhanced migration, invasion, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) phenotypes, independently of its enzymatic activity. Moreover, TW2.6/LOXL2 significantly increased tumor-initiating frequency in SCID mice. We further demonstrated that LOXL2 increased the levels of interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and IFIT3 in TW2.6/LOXL2 and FaDu/LOXL2 cells. We also identified IFIT1 and IFIT3 as key downstream components of LOXL2 action in migration, invasion, EMT, and CSC phenotypes in TW2.6 and FaDu cells. Furthermore, a significant positive correlation between LOXL2 expression and IFIT1 and IFIT3 overexpression in human OSCC tissues was observed. In addition, TW2.6/LOXL2 and FaDu/LOXL2 cells were 3.3- to 3.6-fold more susceptible to the epidermal growth factor receptor (EGFR) inhibitor gefitinib than were their respective control cells. The antitumor effect of gefitinib on orthotopic TW2.6/LOXL2 xenograft tumor was fourfold higher than that on controls. Our results indicate that LOXL2 expression is a strong prognostic factor for OSCC and may be used as a marker to identify patients most likely to respond to EGFR-targeted therapy.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>37496288</pmid><doi>10.1111/cas.15912</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-2976-6195</orcidid><orcidid>https://orcid.org/0000-0001-8321-2575</orcidid><orcidid>https://orcid.org/0000-0002-3247-2585</orcidid><orcidid>https://orcid.org/0000-0003-4674-4892</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antitumor activity Cancer Cell migration Clinical outcomes Enzymatic activity Epidermal growth factor receptors Extracellular matrix Gefitinib Head & neck cancer Interferon Labeling Lymph nodes Lymphatic system Lysyl oxidase Medical prognosis Metastases Metastasis Oral carcinoma Oral squamous cell carcinoma Original ORIGINAL ARTICLES Phenotypes Plasmids Polyclonal antibodies Proteins Survival analysis Tumors |
| title | Lysyl oxidase-like 2 promotes stemness and enhances antitumor effects of gefitinib in head and neck cancer via IFIT1 and IFIT3 |
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