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PRAD6A promotes lung adenocarcinoma cell proliferation and invasion through Serpina3

Cancer Gene Therapy (2024)Cite this article

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Abstract

Par6α encoded by PARD6A is a member of the PAR6 family and is reported to promote cancer initiation and progression. PARD6A is frequently upregulated in different types of cancers, but its regulatory role in lung cancer progression is yet to be established. In this study, we analyzed the PARD6A expression in biopsies from lung adenocarcinoma (LUAD) patients, and the survival probability using LUAD tissue microarray (TMA) and online datasets from TCGA and GEO. We conducted in vitro and in vivo assays to assess the role of PARD6A in regulating lung cancer progression, including proliferation, wound healing, transwell, RNA-seq, and subcutaneous tumor mice models. Our findings revealed that PARD6A is highly expressed in cancer tissues from LUAD patients and is associated with poor prognosis in LUAD patients. In vitro assays showed that PARD6A promoted cell proliferation, migration, and invasion. The transcriptome sequencing identified Serpina3 as one of the key downstream molecules of PARD6A. Ectopic expression of Serpina3 rescued impaired proliferation, migration, and invasion in PARD6A-knocking down H1299 cells, whereas silencing Serpina3 impeded enhanced proliferation, migration, and invasion in PARD6A-overexpressing H1975 cells. Our findings suggest that PARD6A promotes lung cancer progression by inducing Serpina3, which may be a promising therapeutic target.

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Fig. 1: High level of PARD6A is associated with poor prognosis in LUAD patients.
Fig. 2: Blockade of PARD6A inhibits the proliferation, migration, and invasion of H1299 cells.
Fig. 3: PARD6A promotes the proliferation, migration, and invasion of H1975 cells.
Fig. 4: RNA-seq analysis of PARD6A overexpressing H1975 and control cells.
Fig. 5: Serpina3 restores the migration and invasion of PARD6A knock-down H1299 cells.
Fig. 6: Silencing Serpina3 impairs the migration and invasion of PARD6A overexpressing H1975 cells.

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Data availability

The RNA-seq data based on the pan-Cancer Atlas run of the TCGA were obtained from the cBioPortal (https://www.cbioportal.org/). The data used for analyzing clinicopathological association are downloaded from GEO or TCGA database. The remaining data are available within the Article or Supplementary Information. Data will be made available upon request to the corresponding author.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (Grant No. 2023YFC3402100) and the National Natural Science Foundation of China (Grant No. 92259102).

Author information

Author notes

  1. These authors contributed equally: Lanlin Hu, Mingxin Liu, Bo Tang.

  2. These authors jointly supervised this work: Sijia Liu, Chuan Xu.

Authors and Affiliations

  1. Yu-Yue Pathology Scientific Research Center, Chongqing, 400039, China

    Lanlin Hu, Huani Wang & Chuan Xu

  2. Jinfeng Laboratory, Chongqing, 401329, China

    Lanlin Hu, Huani Wang & Chuan Xu

  3. Department of Oncology & Cancer Institute, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China

    Lanlin Hu, Bo Tang, Huani Wang, Dandan Wang & Chuan Xu

  4. Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, 610042, China

    Mingxin Liu

  5. Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400716, China

    Xurui Li

  6. Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China

    Xurui Li

  7. Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Key Laboratory of Regenerative Medicine & Guangxi Engineering Center in Biomedical Material for Tissue and Organ Regeneration & Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, 530021, China

    Huasheng Xu & Sijia Liu

  8. Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China

    Dandan Wang & Chuan Xu

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Contributions

LH and BT established stable knock-down and overexpressing cell lines and performed all in vitro experiments; LH and ML performed in vivo experiments; BT and DW performed bioinformatic analyses; HX and HW reconstructed knock-down and overexpression plasmids; LH, ML, BT, and XL analyzed all data and organized figures; LH, SL, and CX designed and supervised experiments; CX obtained the fundings; LH wrote the paper. All authors read and commented on the paper.

Corresponding authors

Correspondence to Sijia Liu or Chuan Xu.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The tumor tissue microarray (TMA) was purchased from Outdo Biotech Co., Ltd. (China). The study using the TMA was approved by the Life Sciences Ethics Committee of Outdo Biotech Co., Ltd., under the reference number: YB M-05-02. All patients and healthy donors provided informed consent to participate.

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Supplementary information

Table S1. Clinical and pathological information for GSE87340 in the study

Table S2. Clinical and pathological information for GSE63459 in the study

Table S3. Clinical and pathological information for GSE42127 in the study

Table S4. Clinical and pathological information for GSE41271 in the study

Table S5 Clinical and pathological information for TCGA in the study

Table S6 Clinical and pathological information for GSE13522 in the study

Table S7 Clinical and pathological information for GSE126044 in the study

Table S8. Clinicopathological characteristics of PARD6A expression on LUAD tissue microarray

Table S9. Differentially expressed gene (DEGs) List

Table S10. The list of enriched Gene Ontology Biological Process (GO-BP) analysis

Table S11.The list of enriched Gene Ontology Cellular Component (GO- CC) analysis

Table S12. The list of enriched Gene Ontology Molecular function (GO- MF) analysis

Table S13.The list of enriched KEGG pathway analysis

Table S14. The annotation of STRING node

Table S15. The STRING interactions

supplementary Figure 1

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supplementary Figure 5

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Hu, L., Liu, M., Tang, B. et al. PRAD6A promotes lung adenocarcinoma cell proliferation and invasion through Serpina3. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00829-w

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