Cell-type-specific alternative polyadenylation promotes oncogenic gene expression in non-small cell lung cancer progression

Kexin Huang; Yun Zhang; Xiaorui Shi; Zhiqin Yin; Weiling Zhao; Liyu Huang; Fu Wang; Xiaobo Zhou

doi:10.1016/j.omtn.2023.08.005

Cell-type-specific alternative polyadenylation promotes oncogenic gene expression in non-small cell lung cancer progression

Mol Ther Nucleic Acids. 2023 Aug 11:33:816-831. doi: 10.1016/j.omtn.2023.08.005. eCollection 2023 Sep 12.

Authors

Kexin Huang^{1

2

3}, Yun Zhang¹, Xiaorui Shi¹, Zhiqin Yin¹, Weiling Zhao³, Liyu Huang¹, Fu Wang^{1

4}, Xiaobo Zhou³

Affiliations

¹ School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710071, China.
² West China Biomedical Big Data Centre, West China Hospital of Sichuan University, Chengdu 610041, China.
³ Center for Computational Systems Medicine, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁴ School of Pharmacy, Shaanxi Institute of International Trade and Commerce, Xianyang, Shaanxi 712046, China.

Abstract

Disrupted alternative polyadenylation (APA) is frequently involved in tumorigenesis and cancer progression by regulating the gene expression of oncogenes and tumor suppressors. However, limited knowledge of tumor-type- and cell-type-specific APA events may lead to novel APA events and their functions being overlooked. Here, we compared APA events across different cell types in non-small cell lung cancer (NSCLC) and normal tissues and identified functionally related APA events in NSCLC. We found several cell-specific 3'-UTR alterations that regulate gene expression changes showed prognostic value in NSCLC. We further investigated the function of APA-mediated 3'-UTR shortening through loss of microRNA (miRNA)-binding sites, and we identified and experimentally validated several oncogene-miRNA-tumor suppressor axes. According to our analyses, we found SPARC as an APA-regulated oncogene in cancer-associated fibroblasts in NSCLC. Knockdown of SPARC attenuates lung cancer cell invasion and metastasis. Moreover, we found high SPARC expression associated with resistance to several drugs except cisplatin. NSCLC patients with high SPARC expression could benefit more compared to low-SPARC-expression patients with cisplatin treatment. Overall, our comprehensive analysis of cell-specific APA events shed light on the regulatory mechanism of cell-specific oncogenes and provided opportunities for combination of APA-regulated therapeutic target and cell-specific therapy development.

Keywords: MT: Bioinformatics and single-cell RNA sequencing; alternative polyadenylation; drug resistance; non-small cell lung cancer; oncogenic gene expression; prognosis.