Lysosome-related genes: A new prognostic marker for lung adenocarcinoma

Currently, a reliable early prognostic marker has not been identified for lung adenocarcinoma (LUAD), the most common malignancy. Recent studies demonstrated that lysosomal rupture is involved in cancer migration, progression, and immune microenvironment formation. We performed a bioinformatics analysis of lysosomal rupture to investigate whether lysosome-related genes (LRGs) are key in LUAD. The analysis identified 23 LRGs. Cytoscape visualization identified 10 core genes (CCNA2, DLGAP5, BUB1B, KIF2C, PBK, CDC20, NCAPG, ASPM, KIF4A, ANLN). With the 23 LRGs, we established a new risk scoring rule to classify patients with LUAD into high- and low-risk groups and verified the accuracy of the risk score by receiver operating characteristic curves and established a nomogram to evaluate clinical patients. Immunotherapy effectiveness between the high- and low-risk groups was evaluated based on the tumor mutational burden and analyses of immune cell infiltration and drug sensitivity. Pathway enrichment analysis revealed that lysosomes were closely associated with glucose metabolism, amino acid metabolism, and the immune response in patients with LUAD. Lysosomes are a likely new therapeutic target and provide new directions and ideas for treating and managing patients with LUAD.

[1]  A. Ardizzoni,et al.  Predictors of Survival to Immunotherapy and Chemoimmunotherapy in Non-Small Cell Lung Cancer: A Meta-Analysis. , 2022, Journal of the National Cancer Institute.

[2]  C. Hung,et al.  NPRL2 down‐regulation facilitates the growth of hepatocellular carcinoma via the mTOR pathway and autophagy suppression , 2022, Hepatology communications.

[3]  I. Wistuba,et al.  Predictive Biomarkers for Immunotherapy in Lung Cancer: Perspective from the IASLC Pathology Committee. , 2022, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[4]  Milad Soleimani,et al.  Covalent JNK inhibitor, JNK-IN-8, suppresses tumor growth in triple-negative breast cancer by activating TFEB and TFE3 mediated lysosome biogenesis and autophagy. , 2022, Molecular cancer therapeutics.

[5]  Ting Liu,et al.  Development of Strigolactones as Novel Autophagy/Mitophagy Inhibitors against Colorectal Cancer Cells by Blocking the Autophagosome-Lysosome Fusion. , 2022, Journal of medicinal chemistry.

[6]  Taritsa Iulianna,et al.  The Achilles’ heel of cancer: targeting tumors via lysosome-induced immunogenic cell death , 2022, Cell Death & Disease.

[7]  A. Jemal,et al.  Cancer statistics, 2022 , 2022, CA: a cancer journal for clinicians.

[8]  Yongning Zhou,et al.  Circular RNA Circ-0002570 Accelerates Cancer Progression by Regulating VCAN via MiR-587 in Gastric Cancer , 2021, Frontiers in Oncology.

[9]  BTK Inhibitors Show Similar Benefits in CLL. , 2021, Cancer Discovery.

[10]  Rong Li,et al.  miR-543 impairs cell proliferation, migration, and invasion in breast cancer by suppressing VCAN. , 2021, Biochemical and biophysical research communications.

[11]  Yuan-Fei Liu,et al.  INHBA promotes the proliferation, migration and invasion of colon cancer cells through the upregulation of VCAN , 2021, The Journal of international medical research.

[12]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[13]  Xiaojun Huang,et al.  Lysosome-Mediated Cytotoxic Autophagy Contributes to Tea Polysaccharide-Induced Colon Cancer Cell Death via mTOR-TFEB Signaling. , 2020, Journal of agricultural and food chemistry.

[14]  Guo-Dong Lu,et al.  Quercetin induces p53‐independent cancer cell death through lysosome activation by the transcription factor EB and Reactive Oxygen Species‐dependent ferroptosis , 2020, British journal of pharmacology.

[15]  Ru Chen,et al.  Glycogen phosphorylase B promotes cell proliferation and migration through PI3K/AKT pathway in non-small cell lung cancer , 2020, Experimental lung research.

[16]  Wenmei Su,et al.  Lnc-MAP6-1:3 knockdown inhibits osteosarcoma progression by modulating Bax/Bcl-2 and Wnt/β-catenin pathways , 2020, International journal of medical sciences.

[17]  I. Kang,et al.  Versican—A Critical Extracellular Matrix Regulator of Immunity and Inflammation , 2020, Frontiers in Immunology.

[18]  Xia Li,et al.  Sialidase NEU1 suppresses progression of human bladder cancer cells by inhibiting fibronectin-integrin α5β1 interaction and Akt signaling pathway , 2020, Cell Communication and Signaling.

[19]  K. Nagashima,et al.  A FLCN-TFE3 Feedback Loop Prevents Excessive Glycogenesis and Phagocyte Activation by Regulating Lysosome Activity. , 2020, Cell reports.

[20]  S. Tomida,et al.  Impact of EGFR-TKI Treatment on the Tumor Immune Microenvironment in EGFR Mutation–Positive Non–Small Cell Lung Cancer , 2020, Clinical Cancer Research.

[21]  S. Toyooka,et al.  Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small cell lung cancer. , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[22]  A. Ballabio,et al.  Lysosomes as dynamic regulators of cell and organismal homeostasis , 2019, Nature Reviews Molecular Cell Biology.

[23]  Z. Radisavljevic Lysosome activates AKT inducing cancer and metastasis , 2019, Journal of cellular biochemistry.

[24]  M. Bobrowicz,et al.  Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy , 2018, International journal of molecular sciences.

[25]  Chad J. Creighton,et al.  TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins , 2018, Nature Communications.

[26]  S. Wilkinson,et al.  Autophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins , 2017, Nature Communications.

[27]  Yang I Li,et al.  An Expanded View of Complex Traits: From Polygenic to Omnigenic , 2017, Cell.

[28]  J. Bonifacino,et al.  Mechanisms and functions of lysosome positioning , 2016, Journal of Cell Science.

[29]  M. Zhang,et al.  GPC5, a novel epigenetically silenced tumor suppressor, inhibits tumor growth by suppressing Wnt/β-catenin signaling in lung adenocarcinoma , 2016, Oncogene.

[30]  Siwei Wang,et al.  Glypican-5 suppresses Epithelial-Mesenchymal Transition of the lung adenocarcinoma by competitively binding to Wnt3a , 2016, Oncotarget.

[31]  Roberto Zoncu,et al.  The Lysosome as a Regulatory Hub. , 2016, Annual review of cell and developmental biology.

[32]  N. Reinmuth,et al.  Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[33]  G. Bepler,et al.  β-arrestin-1 mediates nicotine-induced metastasis through E2F1 target genes that modulate epithelial-mesenchymal transition. , 2015, Cancer research.

[34]  G. Getz,et al.  Inferring tumour purity and stromal and immune cell admixture from expression data , 2013, Nature Communications.

[35]  N. Perkins,et al.  The diverse and complex roles of NF-κB subunits in cancer , 2012, Nature Reviews Cancer.

[36]  Nan Li,et al.  Adaptor protein LAPF recruits phosphorylated p53 to lysosomes and triggers lysosomal destabilization in apoptosis. , 2007, Cancer research.

[37]  H. Zou The Adaptive Lasso and Its Oracle Properties , 2006 .

[38]  V. Vetvicka,et al.  Role of enzymatically inactive procathepsin D in lung cancer. , 2004, Anticancer research.

[39]  E. Harhaj,et al.  Regulation of the NF-κB-inducing Kinase by Tumor Necrosis Factor Receptor-associated Factor 3-induced Degradation* , 2004, Journal of Biological Chemistry.

[40]  J. Lotem,et al.  Lysosomal destabilization in p53-induced apoptosis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. Stewart,et al.  Review Wnt Signaling Pathway in Non–small Cell Lung Cancer Overview of the Wnt Canonical (β-catenin) and Noncanonical Signaling Pathways , 2022 .