Endoplasmic reticulum–resident α-glucosidase II drives non-small cell lung cancer progression via regulation of secretory glycoproteins
Shike Wang, Na Ding, Angelo Chen, Derrick Cardin, Yuting Xu, Kate Grimley, William K. Russell, Jun Xu, Jonathan M. Kurie, Guan-Yu Xiao, Xiaochao Tan
Shike Wang, Na Ding, Angelo Chen, Derrick Cardin, Yuting Xu, Kate Grimley, William K. Russell, Jun Xu, Jonathan M. Kurie, Guan-Yu Xiao, Xiaochao Tan
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Research Article Cell biology Oncology

Endoplasmic reticulum–resident α-glucosidase II drives non-small cell lung cancer progression via regulation of secretory glycoproteins

Abstract

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, yet its molecular drivers are not fully defined. Emerging evidence highlights the importance of tumor-stroma interactions mediated by secreted glycoproteins. However, the mechanisms by which cancer cells regulate the secretion of these protumorigenic proteins remain largely unknown. Endoplasmic reticulum–resident (ER-resident) N-glycan–processing enzymes regulate proper protein folding, a prerequisite for glycoproteins to exit the ER and undergo secretion. By evaluating their prognostic significance in lung tumors and conducting functional screening in lung cancer cells, we identify α-glucosidase II (α-Glc II) as a key regulator of NSCLC progression. α-Glc II promotes tumor growth and dissemination in a glucosidase activity–dependent manner in orthotopic mouse lung tumor model. Genetic disruption of α-Glc II induced ER stress and reduced cell proliferation and motility. Mechanistically, α-Glc II–mediated N-glycan modification regulated the ER-to-Golgi trafficking and secretion of specific oncogenic glycoproteins, including lysyl hydroxylase 2 (LH2), Tissue Inhibitor of Metalloproteinase 1 (TIMP1), and TGF-β, which are known to be associated with extracellular matrix remodeling. These findings uncover a role for ER glycosylation machinery in shaping the NSCLC secretome and highlight α-Glc II as a potential therapeutic target.

Authors

Shike Wang, Na Ding, Angelo Chen, Derrick Cardin, Yuting Xu, Kate Grimley, William K. Russell, Jun Xu, Jonathan M. Kurie, Guan-Yu Xiao, Xiaochao Tan

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Figure 2

GANAB is a direct target of tumor-suppressive microRNAs (miRNAs).

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GANAB is a direct target of tumor-suppressive microRNAs (miRNAs). (A) Gr...
(A) Graph showing predicted miRNAs binding sites in the 3′ UTR of GANAB (top) and a heatmap showing the relative expression levels of these miRNAs in lung cancer tissues compared with normal tissues (bottom). (B and C) WB analysis of GANAB protein levels in A549 (B) and H460 (C) cells following ectopic expression of indicated miRNAs. Densitometric analysis was performed using ImageJ. (D and E) GANAB 3′-UTR reporter assays. H1299 cells were cotransfected with miR-133a mimics (D) or miR-145 mimics (E) and luciferase reporters containing either WT or miR-133a/miR-145 binding site–mutant 3′-UTRs of GANAB. P values were determined using 2-tailed Student’s t test. (F) Boyden chamber transwell assay on A549 cells cotransfected of miR-133a, miR-145, or negative control (NC) mimics and GANAB expression vector or control vector. P values were determined using 1-way ANOVA. Data indicate the mean ± SEM from a single experiment incorporating biological replicate samples (n ≥ 3) and are representative of at least 2 independent experiments.