Chitinase-3-like protein 1 (CHI3L1), which is secreted by immune and inflammatory cells, is associated with several inflammatory diseases. However, the basic cellular pathophysiological functions of CHI3L1 are not well characterized. To investigate the novel pathophysiological function of CHI3L1, we performed LC-MS/MS analysis of cells transfected with Myc-vector and Myc-CHI3L1. We analyzed the changes in the
protein distribution in Myc-CHI3L1 transfected-cells, and identified 451 differentially expressed
proteins (DEPs) compared with Myc-vector-transfected-cells. The
biological function of the 451 DEPs was analyzed and it was found that the
proteins with endoplasmic reticulum (ER)-associated function were much more highly expressed in CHI3L1-overexpressing cells. We then compared and analyzed the effect of CHI3L1 on the ER chaperon levels in normal lung cells and
cancer cells. We identified that CHI3L1 is localized in the ER. In normal cells, the depletion of CHI3L1 did not induce ER stress. However, the depletion of CHI3L1 induces ER stress and eventually activates the unfolded protein response, especially the activation of
Protein kinase R-like endoplasmic reticulum
kinase (PERK), which regulates
protein synthesis in
cancer cells. CHI3L1 may not affect ER stress owing to the lack of misfolded
proteins in normal cells, but instead activate ER stress as a defense mechanism only in
cancer cells. Under ER stress conditions induced by the application of
thapsigargin, the depletion of CHI3L1 induces ER stress through the upregulation of PERK and PERK downstream factors (eIF2α and ATF4) in both normal and
cancer cells. However, these signaling activations occur more often in
cancer cells than in normal cells. The expression of
Grp78 and PERK in the tissues of patients with
lung cancer was higher compared with healthy tissues. It is well known that ER stress-mediated PERK-eIF2α-ATF4 signaling activation causes apoptotic cell death. ER stress-mediated apoptosis induced by the depletion of CHI3L1 occurs in
cancer cells, but rarely occurs in normal cells. Consistent with results from the in vitro model, ER stress-mediated apoptosis was greatly increased during
tumor growth and in the lung metastatic tissue of CHI3L1-knockout (KO) mice. The analysis of "big data" identified
superoxide dismutase-1 (SOD1) as a novel target of CHI3L1 and interacted with CHI3L1. The depletion of CHI3L1 increased SOD1 expression, resulting in ER stress. Furthermore, the depletion of SOD1 reduced the expression of ER chaperones and ER-mediated apoptotic marker
proteins, as well as apoptotic cell death induced by the depletion of CHI3L1 in in vivo and in vitro models. These results suggest that the depletion of CHI3L1 increases ER stress-mediated apoptotic cell death through SOD1 expression, and subsequently inhibits lung
metastasis.