TY - JOUR
T1 - FOSL1 promotes Kras-induced lung cancer through amphiregulin and cell survival gene regulation
AU - Elangovan, Indira M.
AU - Vaz, Michelle
AU - Tamatam, Chandramohan R.
AU - Potteti, Haranatha R.
AU - Reddy, Narsa M.
AU - Reddy, Sekhar P.
N1 - Funding Information:
This work was supported by National Institutes of Health grants ES18998 and ES11863, and the University of Illinois at Chicago Cancer Center Pilot Project.
Publisher Copyright:
Copyright © 2018 by the American Thoracic Society.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - The FOSL1/AP-1 transcription factor regulates gene expression, thereby controlling various pathophysiological processes. It is a major effector of RAS-ERK1/2 signaling and is activated in human lung epithelia by tumorigenic stimuli. Recent evidence shows an inverse correlation between FOSL1 expression and the survival of patients with lung cancer and adenocarcinomas; however, its role in lung tumorigenesis remains elusive. In this work, we sought to determine the role of FOSL1 in Kras-induced lung adenocarcinoma in vivo and its downstream effector mechanisms. We used mice expressing the Kras oncogene in the lung with concomitant Fosl1 deletion, Kras-activated murine alveolar epithelial cells (mAECs) with Fosl1 deletion, and KRAS mutant human lung adenocarcinoma (HLAC) cells with FOSL1 deficiency, and performed cell proliferation and gene expression analyses. Mutant Kras induced Fosl1 expression in vitro (mAECs) and in vivo (lung tissue), and mice with Fosl1 deletion showed reduced levels of mutant Kras–induced lung tumorigenesis and survived longer than Fosl1-sufficient mice. Studies with mutant Kras–activated mAECs and KRAS-mutant HLAC cells revealed that FOSL1 regulates mutant KRAS–induced gene expression, thereby controlling cell proliferation and survival. In contrast, FOSL1 depletion in non–KRAS-mutant HLAC cells and nonmalignant human lung epithelia had no effect. Our data support the notion that FOSL1-mediated expression of amphiregulin and apoptotic and antioxidative genes plays a role in regulating HLAC cell proliferation and survival. FOSL1 is a determinant of lung cancer in vivo and regulates HLAC cell proliferation and survival, largely in the context of KRAS mutations. Activation of FOSL1 in adenocarcinomas may be a prognostic marker and potential target for human lung cancer with KRAS mutations.
AB - The FOSL1/AP-1 transcription factor regulates gene expression, thereby controlling various pathophysiological processes. It is a major effector of RAS-ERK1/2 signaling and is activated in human lung epithelia by tumorigenic stimuli. Recent evidence shows an inverse correlation between FOSL1 expression and the survival of patients with lung cancer and adenocarcinomas; however, its role in lung tumorigenesis remains elusive. In this work, we sought to determine the role of FOSL1 in Kras-induced lung adenocarcinoma in vivo and its downstream effector mechanisms. We used mice expressing the Kras oncogene in the lung with concomitant Fosl1 deletion, Kras-activated murine alveolar epithelial cells (mAECs) with Fosl1 deletion, and KRAS mutant human lung adenocarcinoma (HLAC) cells with FOSL1 deficiency, and performed cell proliferation and gene expression analyses. Mutant Kras induced Fosl1 expression in vitro (mAECs) and in vivo (lung tissue), and mice with Fosl1 deletion showed reduced levels of mutant Kras–induced lung tumorigenesis and survived longer than Fosl1-sufficient mice. Studies with mutant Kras–activated mAECs and KRAS-mutant HLAC cells revealed that FOSL1 regulates mutant KRAS–induced gene expression, thereby controlling cell proliferation and survival. In contrast, FOSL1 depletion in non–KRAS-mutant HLAC cells and nonmalignant human lung epithelia had no effect. Our data support the notion that FOSL1-mediated expression of amphiregulin and apoptotic and antioxidative genes plays a role in regulating HLAC cell proliferation and survival. FOSL1 is a determinant of lung cancer in vivo and regulates HLAC cell proliferation and survival, largely in the context of KRAS mutations. Activation of FOSL1 in adenocarcinomas may be a prognostic marker and potential target for human lung cancer with KRAS mutations.
KW - AP-1
KW - Apoptosis
KW - Cyclins
KW - Epidermal growth factors
KW - Tumor cell growth
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U2 - 10.1165/rcmb.2017-0164OC
DO - 10.1165/rcmb.2017-0164OC
M3 - Article
C2 - 29112457
AN - SCOPUS:85046668775
SN - 1044-1549
VL - 58
SP - 625
EP - 635
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 5
ER -