HSPA1L Enhances Cancer Stem Cell-Like Properties by Activating IGF1Rβ and Regulating β-Catenin Transcription

Abstract

Studies have shown that cancer stem cells (CSCs) are involved in resistance and metastasis of cancer; thus, therapies targeting CSCs have been proposed. Here, we report that heat shock 70-kDa protein 1-like (HSPA1L) is partly involved in enhancing epithelial–mesenchymal transition (EMT) and CSC-like properties in non-small cell lung cancer (NSCLC) cells. Aldehyde dehydrogenase 1 (ALDH1) is considered a CSC marker in some lung cancers. Here, we analyzed transcriptional changes in genes between ALDH1high and ALDH1low cells sorted from A549 NSCLC cells and found that HSPA1L was highly expressed in ALDH1high cells. HSPA1L played two important roles in enhancing CSC-like properties. First, HSPA1L interacts directly with IGF1Rβ and integrin αV to form a triple complex that is involved in IGF1Rβ activation. HSPA1L/integrin αV complex-associated IGF1Rβ activation intensified the EMT-associated cancer stemness and γ-radiation resistance through its downstream AKT/NF-κB or AKT/GSK3β/β-catenin activation pathway. Secondly, HSPA1L was also present in the nucleus and could bind directly to the promoter region of β-catenin to function as a transcription activator of β-catenin, an important signaling protein characterizing CSCs by regulating ALDH1 expression. HSPA1L may be a novel potential target for cancer treatment because it both enhances IGF1Rβ activation and regulates γβ-catenin transcription, accumulating CSC-like properties.

Hyperelastic, shape‐memorable, and ultra‐cell‐adhesive degradable polycaprolactone‐polyurethane copolymer for tissue regeneration

“…Similar fibronectin adsorption amounts and supraphysiologically high stiffness (30–50 MPa) than pre‐mineralized extracellular matrix were detected in ISB‐P and PCL (Figure S14), reinforcing the involvement of biological factors, here Hsp1a‐induced integrin α5 and αν functional activity, in enhancing stem cell adhesion on ISB‐P 86 . Taken together, these results revealed that the integrin α5 and αν subunit functions as major surface receptors for ISB‐P in stem cells possibly by the activation of Hspa1a in a special biological signaling pathway, 87–89 not by physical factors such as surface roughness and adhesive protein adsorption. Further study is necessary to investigate whether the activation of Hspa1a genes by ISB‐P to regulate cell adhesion is unique among PU‐PCL shape‐memory polymers and what are the key chemical structures to tune Hspa1a genes.…”

Epithelial membrane protein 3 regulates lung cancer stem cells via the TGF‑β signaling pathway

“…Amongst these, a protein that is overexpressed together with a stem cell marker protein is classified as a CSC marker protein (32). In previous experiments, ALDH1 was used as a marker protein to classify overexpressed genes in LCSCs (33). Through classification using the feature extraction software, information on 4,300 genes that were expressed >2x higher in ALDH1 + cells than in the control group was obtained (Fig.…”

Pseudogene HSPA7 is a poor prognostic biomarker in Kidney Renal Clear Cell Carcinoma (KIRC) and correlated with immune infiltrates

“…Accumulating data indicated that HSP70 family can play a causal role in cancer initiation. Evidence showed that HSPA1L can enhance cancer stem cell-like properties via regulating β-Catenin transcription and activating IGF1Rβ [ 25 ]. RNF144A interacted with HSPA2 can promote tumor growth and progression [ 26 ].…”