IQGAP3 activates Hedgehog signaling to confer stemness and metastasis via up-regulating GLI1 in lung cancer.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Zinc Finger Protein GLI1*/metabolism ; Zinc Finger Protein GLI1*/genetics ; Lung Neoplasms*/pathology ; Lung Neoplasms*/metabolism ; Lung Neoplasms*/genetics ; Hedgehog Proteins*/metabolism ; Signal Transduction* ; Neoplastic Stem Cells*/metabolism ; Neoplastic Stem Cells*/pathology ; Gene Expression Regulation, Neoplastic*; Humans ; Cell Line, Tumor ; Cell Movement/genetics ; Neoplasm Metastasis ; Up-Regulation ; Carcinoma, Non-Small-Cell Lung/pathology ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/genetics ; Animals ; ras GTPase-Activating Proteins/metabolism ; ras GTPase-Activating Proteins/genetics ; Mice ; GTPase-Activating Proteins

Lung cancer ranks as the most prevalent malignant neoplasm worldwide, contributing significantly to cancer-related mortality. Stemness is a well-recognized factor underlying radiotherapy resistance, recurrence and metastasis in non-small-cell lung cancer (NSCLC) patients. Our prior investigations have established the role of IQ motif containing GTPase-activating protein 3 (IQGAP3) in mediating radiotherapy resistance in lung cancer, but its impact on lung cancer stemness remains unexplored. Our bioinformatics analysis results revealed a significant correlation between IQGAP3 and lung cancer stemness. Moreover, we found that IQGAP3 depletion in lung cancer cells resulted in reduced migration, invasion and sphere-forming capabilities. Through RNA sequencing, we identified GLI1 as a pivotal downstream effector of IQGAP3. The knockdown of IQGAP3 led to the downregulation of GLI1 mRNA and protein levels, which impeded the activation of the Hedgehog-GLI1 signaling pathway. Further, our results also indicated that GLI1 is the primary effector mediating IQGAP3's biological functions in lung cancer. These findings elucidate the role of IQGAP3 in promoting lung cancer stemness and metastasis through the Hedgehog pathway, facilitated by GLI1, highlighting the potential of IQGAP3 as a promising therapeutic target for lung cancer treatment.
Competing Interests: Declarations. Ethics approval and consent to participate: The present study was approved by the Ethics Committee of Union Hospital of Huazhong University of Science and Technology. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)

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82073179 National Natural Science Foundation of China; 82202953 National Natural Science Foundation of China

Keywords: GLI1; Hedgehog pathway; IQGAP3; Lung cancer; Stemness

0 (Zinc Finger Protein GLI1)
0 (GLI1 protein, human)
0 (Hedgehog Proteins)
0 (IQGAP3 protein, human)
0 (ras GTPase-Activating Proteins)
0 (GTPase-Activating Proteins)

Date Created: 20241229 Date Completed: 20241229 Latest Revision: 20250104

20250114

PMC11682282

10.1038/s41598-024-82793-x

39732803