{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T10:44:59Z","timestamp":1762425899238,"version":"build-2065373602"},"reference-count":29,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The enhancement of cell motility by bioactive molecules such as growth factors, hormones, and tissue factors is pivotal in cancer invasion and metastasis. However, the molecular mechanisms underlying this enhancement remain incompletely understood. In this study, we demonstrate that hepatoblastoma HepG2 cell motility is significantly increased following hepatocyte growth factor (HGF) treatment, as assessed by phagokinetic track assays, Transwell assays, and scratch assays. This enhancement is mediated by reactive oxygen species (ROS), which activate the PKC\u03b6\/Rho GTPase signaling pathway. Notably, the motility increase is markedly suppressed by superoxide dismutase (SOD), N\u2010acetylcysteine (NAC), diphenyleneiodonium (DPI), and the PKC\u03b6 inhibitory peptide MyrPKC\u03b6. Similar patterns of motility enhancement and its inhibition by MyrPKC\u03b6 were observed in HGF\u2010treated colon cancer HCT116 cells, epidermal growth factor (EGF)\u2010treated HepG2 and HCT116 cells, and transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2)\u2010treated HepG2 cells, as evaluated using Transwell assays. Additionally, estradiol enhances the motility of breast cancer MDA\u2010MB\u2010231\u2010luc cells via ROS generation and activation of the PKC\u03b6\/Rho GTPase signaling pathway, with this effect significantly suppressed by MyrPKC\u03b6 in Transwell assays. The inhibitory effect of MyrPKC\u03b6 was further confirmed in\u00a0vivo, where it suppressed peritoneal invasion of HCT116 cells in NOD\u2010SCID mice. Furthermore, in NOD\u2010SCID mice injected with MDA\u2010MB\u2010231\u2010luc cells carrying shRNA targeting PKC\u03b6 into the tail vein, doxycycline\u2010induced shRNA expression resulted in marked suppression of pulmonary metastasis. These findings indicate that the ROS\/PKC\u03b6\/Rho GTPase signaling cascade is a pivotal regulator of cancer cell motility and suggest that PKC\u03b6 represents a promising therapeutic target for preventing cancer invasion and metastasis.<\/jats:p>","DOI":"10.1111\/cas.70165","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T16:40:02Z","timestamp":1755708002000},"page":"3027-3039","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ROS\u2010Driven PKC\u03b6 Signaling as a Widely Involved Mechanism for Cancer Cell Motility and Metastasis"],"prefix":"10.1111","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6776-4609","authenticated-orcid":false,"given":"Yasushi","family":"Sato","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Oncology Institute of Health Biosciences, University of Tokushima Graduate School  Tokushima Japan"},{"name":"4th Department of Internal Medicine; Renamed as Department of Clinical Oncology Sapporo Medical University, School of Medicine  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"4th Department of Internal Medicine; Renamed as Department of Clinical Oncology Sapporo Medical University, School of Medicine  Sapporo Japan"},{"name":"Department of Clinical Laboratory Science School of Medical Technology, Health Sciences University of Hokkaido  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoko","family":"Kitamura","sequence":"additional","affiliation":[{"name":"Department of Molecular Target Exploration Sapporo Medical University, School of Medicine  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoko","family":"Araki","sequence":"additional","affiliation":[{"name":"4th Department of Internal Medicine; Renamed as Department of Clinical Oncology Sapporo Medical University, School of Medicine  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wataru","family":"Kurata","sequence":"additional","affiliation":[{"name":"Clinical Cancer Research Division Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Shonan Health Innovation Park  Fujisawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akiko","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Clinical Cancer Research Division Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Shonan Health Innovation Park  Fujisawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukimi","family":"Seo","sequence":"additional","affiliation":[{"name":"Clinical Cancer Research Division Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Shonan Health Innovation Park  Fujisawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kageaki","family":"Kuribayashi","sequence":"additional","affiliation":[{"name":"4th Department of Internal Medicine; Renamed as Department of Clinical Oncology Sapporo Medical University, School of Medicine  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuzo","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Clinical Cancer Research Division Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Shonan Health Innovation Park  Fujisawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiro","family":"Niitsu","sequence":"additional","affiliation":[{"name":"Department of Molecular Target Exploration Sapporo Medical University, School of Medicine  Sapporo Japan"},{"name":"Clinical Cancer Research Division Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Shonan Health Innovation Park  Fujisawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460\u20102075.1991.tb07836.x"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/175883401142255"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010022\u201001503\u20101"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ircmb.2014.10.001"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010024\u201001764\u2010w"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12672\u2010010\u20100055\u20101"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2010\u20100252"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017218"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.279.5350.509"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010021\u201001960\u20104"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1116833"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00147.2006"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/19420889.2015.1074360"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.05.003"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010025\u201001617\u2010w"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.618261"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008045"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvab171"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14528"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010017\u201002357\u20108"},{"issue":"24","key":"e_1_2_11_22_1","first-page":"6210","article-title":"Superoxide Dismutase in SAS Human Tongue Carcinoma Cell Line Is a Factor Defining Invasiveness and Cell Motility","volume":"55","author":"Muramatsu H.","year":"1995","journal-title":"Cancer Research"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1023\/a:1006633616629"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910570226"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200607019"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.46.30306"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2011.226"},{"issue":"2","key":"e_1_2_11_28_1","first-page":"521","article-title":"Estrogen and Anti\u2010Estrogen Responses in ER\u2010Negative Breast Cancer Cell Lines","volume":"31","author":"Ford C. 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