TY - JOUR
T1 - FCN3 functions as a tumor suppressor of lung adenocarcinoma through induction of endoplasmic reticulum stress
AU - Jang, Haeyeon
AU - Jun, Yukyung
AU - Kim, Suyeon
AU - Kim, Eunjeong
AU - Jung, Yeonjoo
AU - Park, Byung Jo
AU - Lee, Jinseon
AU - Kim, Jhingook
AU - Lee, Sanghyuk
AU - Kim, Jaesang
N1 - Funding Information:
This work was supported by the National Research Foundation of Korea (NRF-2015K1A4A3047851 & 2020R1F1A1071062) funded by the Ministry of Scienceand ICT, Republic of Korea.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/4
Y1 - 2021/4
N2 - In this study, we report a novel function of FCN3 (Ficolin 3), a secreted lectin capable of activating the complement pathway, as a tumor suppressor of lung adenocarcinoma (LUAD). First, the expression of FCN3 was strongly down-regulated in cancer tissues compared to matched normal lung tissues, and down-regulation of FCN3 was shown to be significantly correlated with increased mortality among LUAD patients. Interestingly, while ectopic expression of FCN3 led to cell cycle arrest and apoptosis in A549 and H23 cells derived from LUAD, the secreted form of the protein had no effect on the cells. Rather, we found evidence indicating that activation of the unfolded protein response from endoplasmic reticulum (ER) stress is induced by ectopic expression of FCN3. Consistently, inhibition of ER stress response led to enhanced survival of the LUAD cells. Of note, the fibrinogen domain, which is not secreted, turned out to be both necessary and sufficient for induction of apoptosis when localized to ER, consistent with our proposed mechanism. Collectively, our data indicate that FCN3 is a tumor suppressor gene functioning through induction of ER stress.
AB - In this study, we report a novel function of FCN3 (Ficolin 3), a secreted lectin capable of activating the complement pathway, as a tumor suppressor of lung adenocarcinoma (LUAD). First, the expression of FCN3 was strongly down-regulated in cancer tissues compared to matched normal lung tissues, and down-regulation of FCN3 was shown to be significantly correlated with increased mortality among LUAD patients. Interestingly, while ectopic expression of FCN3 led to cell cycle arrest and apoptosis in A549 and H23 cells derived from LUAD, the secreted form of the protein had no effect on the cells. Rather, we found evidence indicating that activation of the unfolded protein response from endoplasmic reticulum (ER) stress is induced by ectopic expression of FCN3. Consistently, inhibition of ER stress response led to enhanced survival of the LUAD cells. Of note, the fibrinogen domain, which is not secreted, turned out to be both necessary and sufficient for induction of apoptosis when localized to ER, consistent with our proposed mechanism. Collectively, our data indicate that FCN3 is a tumor suppressor gene functioning through induction of ER stress.
UR - http://www.scopus.com/inward/record.url?scp=85104311253&partnerID=8YFLogxK
U2 - 10.1038/s41419-021-03675-y
DO - 10.1038/s41419-021-03675-y
M3 - Article
C2 - 33859174
AN - SCOPUS:85104311253
SN - 2041-4889
VL - 12
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 4
M1 - 407
ER -