Cullin 3 overexpression inhibits lung cancer metastasis and is associated with survival of lung adenocarcinoma

• Published in: Clinical & experimental metastasis 2020-02, Vol.37 (1), p.115-124
• Main Authors: Zhou, Jiayu, Zhang, Shizhen, Xu, Yong, Ye, Weiwen, Li, Zhijun, Chen, Zhoumiao, He, Zhengfu
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma of Lung - pathology; Adenocarcinoma of Lung - secondary; Animals; Biological activity; Biomarkers; Biomarkers, Tumor - analysis; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Breast; Breast cancer; Cancer Research; Carcinogenesis - pathology; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - secondary; Cell Line, Tumor; Cell migration; Cell Movement; Cell Proliferation; Cell survival; Cullin; Cullin Proteins - analysis; Cullin Proteins - metabolism; Data bases; Female; Gene expression; Gene Knockdown Techniques; Hematology; Humans; Immunoblotting; Immunohistochemistry; Kaplan-Meier Estimate; Lung cancer; Lung carcinoma; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Medical prognosis; Metastases; Metastasis; Mice; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Non-small cell lung carcinoma; Oncology; Prognosis; Research Paper; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; RhoA protein; RNA, Small Interfering - metabolism; Signal Transduction - genetics; Small cell lung carcinoma; Squamous cell carcinoma; Substrates; Surgical Oncology; Survival; Tissue analysis; Tissues; Tumor cell lines; Tumorigenesis; Tumorigenicity; Ubiquitin; Ubiquitin-protein ligase; Xenograft Model Antitumor Assays
• ISSN: 0262-0898; 1573-7276
• DOI: 10.1007/s10585-019-09988-9

Cullin 3 (CUL3), a molecular scaffold of Cullin-RING ubiquitin ligase, plays an important role in regulating biological processes through modulating the ubiquitylation and degradation of various protein substrates. Dysfunction of CUL3 is implicated in the development of several human diseases. However, the clinical significance and prognostic value of CUL3 in lung cancer have not been investigated. This study investigated the CUL3-modulating potential of non-small cell lung cancer cell lines, H1299, H358, H2170 and H520, by using immunoblotting, MTT, migration, invasion, colony formation and in vivo tumorigenicity assays. The prognostic significance of CUL3 was measured by public KM plotter database ( http://kmplot.com/analysis/index.php?p=service&cancer=breast ) and tissue immunohistochemistry analysis. The public online database analysis revealed that elevated mRNA expression of CUL3 was associated with better prognosis for non-small cell lung cancer and lung adenocarcinoma. In vitro experiments showed that ectopic overexpression of CUL3 significantly inhibited lung adenocarcinoma cell proliferation and migration, and the tumor-suppressive effect of CUL3 was dependent on the Nrf2/RhoA axis. In vivo mice model demonstrated that overexpression of CUL3 lead to a significant reduction of lung adenocarcinoma growth and metastasis. Importantly, tissue immunohistochemistry analysis showed that about 47% of non-small cell lung cancer tissues were expressed of CUL3 at high levels. Overexpression of CUL3 predicted favorable overall survival in non-small cell lung cancer patients, especially in lung adenocarcinoma, but not in lung squamous cell carcinoma patients. CUL3 could serve as a prognostic biomarker for lung adenocarcinoma. Loss of CUL3 might be driving tumorigenesis by activating the Nrf2/RhoA pathway.