2. Academic Validation
  3. ANKRD49 promotes the metastasis of NSCLC via activating JNK-ATF2/c-Jun-MMP-2/9 axis

ANKRD49 promotes the metastasis of NSCLC via activating JNK-ATF2/c-Jun-MMP-2/9 axis

  • BMC Cancer. 2023 Nov 14;23(1):1108. doi: 10.1186/s12885-023-11612-9.
Jia Sun # 1 2,  Jin-Rui Hu # 3,  Chao-Feng Liu # 1,  Yuan Li 4,  Wei Wang 3,  Rong Fu 3,  Min Guo 5,  Hai-Long Wang 6,  Min Pang 7 8
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine, Shanxi Province Key Laboratory of Respiratory Disease, the First Hospital, Shanxi Medical University, NHC Key Laboratory of Pneumoconiosis, Taiyuan, Shanxi, 030001, China.
  • 2 Department of Laboratorial Medicine, Changzhi Traditional Chinese Medicine Hospital, Changzhi, 046000, China.
  • 3 School of Basic Medicine, Basic Medical Sciences Center, Shanxi Medical University, No. 55 Wenhua Street, Jinzhong, Shanxi, 030600, China.
  • 4 Department of Respiratory Medicine 1, Shanxi Hospital Affiliated to Cancer Hospital, Shanxi Province Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, China.
  • 5 Laboratory of Animal Center, Shanxi Medical University, Taiyuan, 030001, China.
  • 6 School of Basic Medicine, Basic Medical Sciences Center, Shanxi Medical University, No. 55 Wenhua Street, Jinzhong, Shanxi, 030600, China. longwty@163.com.
  • 7 Department of Pulmonary and Critical Care Medicine, Shanxi Province Key Laboratory of Respiratory Disease, the First Hospital, Shanxi Medical University, NHC Key Laboratory of Pneumoconiosis, Taiyuan, Shanxi, 030001, China. pangmin2009@126.com.
  • 8 Department of Pulmonary and Critical Care Medicine, the First Hospital, Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, Shanxi, 030001, China. pangmin2009@126.com.
  • # Contributed equally.
PMID: 37964204 DOI: 10.1186/s12885-023-11612-9
Abstract

Background: Ankyrin repeat domain 49 (ANKRD49) has been found to be highly expressed in multiple Cancer including lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC). However, the function of ANKRD49 in the pathogenesis of NSCLC still remains elusive. Previously, ANKRD49 has been demonstrated to promote the invasion and metastasis of A549 cells, a LUAD cell line, via activating the p38-ATF-2-MMP2/MMP9 pathways. Considering the heterogeneity of tumor cells, the function and mechanism of ANKRD49 in NSCLC need more NSCLC-originated cells to clarify.

Methods: Real-time qPCR was employed to test ANKRD49 expression levels in nine pairs of fresh NSCLC tissues and the corresponding adjacent normal tissues. The function of ANKRD49 was investigated using overexpression and RNA interference assays in lung adenocarcinoma cell line (NCI-H1299) and lung squamous carcinoma cell line (NCI-H1703) through gelatin zymography, cell counting kit-8, colony formation, wound healing, migration and invasion assays mmunoprecipitation was performed to in vitro. Immunoprecipitation was performed to test the interaction of c-Jun and ATF2. Chromatin immunoprecipitation was conducted to assess the transcriptional regulation of ATF2/c-Jun on MMP-2/9. Moreover, the tumorigenicity of ANKRD49 was evaluated in nude mice models and the involved signal molecular was also measured by immunohistochemical method.

Results: We found that the levels of ANKRD49 in cancerous tissues were higher than those in adjacent normal tissues. in vitro assay showed that ANKRD49 promoted the migration and invasion of NCI-H1299 and NCI-H1703 cells via enhancing the levels of MMP-2 and MMP-9. Furthermore, ANKRD49 elevated phosphorylation of JNK and then activated c-Jun and ATF2 which interact in nucleus to promote the binding of ATF2:c-Jun with the promoter MMP-2 or MMP-9. In vivo assay showed that ANKRD49 promoted lung metastasis of injected-NSCLC cells and the high metastatic rate was positively correlated with the high expression of ANKRD49, MMP-2, MMP-9, p-JNK, p-c-Jun and p-ATF2.

Conclusion: The present study indicated that ANKRD49 accelerated the invasion and metastasis of NSCLC cells via JNK-mediated transcription activation of c-Jun and ATF2 which regulated the expression of MMP-2/MMP-9. The molecular mechanisms of ANKRD49's function is different from those found in A549 cells. The current study is a supplement and improvement to the previous research.

Keywords

ANKRD49; ATF2; Matrix metalloproteinases; Metastasis; c-Jun.

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