Autophage activation by tol-like receptors has been reported to contribute to the proliferation and metastasis of cancer cells and cancer stem cells (CSCs) present in lung cancer microenvironments, which is considered one of the causes of resistance to various chemotherapy. The mechanism study presented in this study is expected to contribute to the identification of pathological causes and new anti-cancer treatment strategies for the development and progression of lung cancer.
Prof. LEE, KI YOUNG
Mi Jung Kim, Ji Soo Lee, Ji Young Kim
Cereblon (CRBN) has been identified as a primary target of immunomodulatory drugs in multiple myeloma. Herein, for the first time, we demonstrate that CRBN expression is functionally involved in lung cancer progression through the regulation of autophagy by toll‐like receptor (TLR)2, TLR4 and TLR7. TLR signalling is associated with the induction of autophagy and plays a pivotal role in the progression and pathogenesis of lung cancer.
The onset and development of lung cancer are regulated by a variety of external and internal factors that influence the tumor microenvironment (TME). The downregulation or upregulation of genes in lung cancer cells is highly likely to be implicated in the pathogenesis and progression of lung cancer.
In this study, we show that CRBN is downregulated in lung cancer cells and associated with lung cancer progression. Notably, we found that CRBN inhibits the BECN1 ubiquitination to induce autophagy and attenuates the production of IL‐6, CCL2, CCL20 and MMP2 cytokines in response to TLR stimulations in healthy lung cells expressing CRBN (Figure 1). In lung cancer cells with downregulated CRBN (Figure 1), engagements of TLRs enhance autophagy induction through the increases of BECN1 ubiquitination and the production of IL‐6, CCL2, CCL20 and MMP2 cytokines, eventually facilitating lung cancer progression.
Taken together, our clinically comparative results and functional investigations of CRBN in lung cancer progression will potentially contribute to translational approaches for lung cancer intervention. Additionally, CRBN can be a potent prognostic marker for lung cancer and provides important implications in clinical and translational lung cancer biology.
Article: Kim MJ, Lee JS, Kim JY, Choi B, Son J, Min Y, Jeong SK, Kim DH, Lee JS, Chun E, Lee KY. CRBN is downregulated in lung cancer and negatively regulates TLR2, 4 and 7 stimulation in lung cancer cells. Clinical and translational medicine (IF: 11.492). 2022 Sep;12(9):e1050.