PARProceedings of Anticancer Research2208-35452208-3553Bio-Byword Scientific Publishing Pty. Ltd.10.26689/par.v9i3.10571ArticleLINC00936 Suppresses Non-Small Cell Lung Cancer Progression Through Modulation of the Ras/MAPK Signaling Pathwayhttps://artdesignp.com/journal/PAR/9/3/10.26689/par.v9i3.10571ChenYang,DuLin2025932025-05-29Objective: To characterize the tumor-suppressive role of LINC00936 in non-small cell lung cancer (NSCLC) through mechanistic exploration of its regulatory pathways. Methods: Bioinformatics interrogation of TCGA/NSCLC cohorts assessed LINC00936 expression, clinical correlations, and immune contexture. Functional enrichment analyses predicted pathway associations. In H1299 cells, LINC00936 overexpression (plasmid) and knockdown (siRNA) models were validated by RT-qPCR. Transcriptomic profiling identified differentially expressed genes (DEGs) subjected to KEGG pathway analysis. Results: LINC00936 was significantly downregulated in NSCLC tissues (TCGA, P < 0.05) and cell lines (vs. 16-HBE, P < 0.05), correlating with poor prognosis and altered tumor-infiltrating immune subsets. DEG enrichment implicated Ras/MAPK signaling as the dominant pathway (FDR < 0.05). Successful LINC00936 modulation (overexpression/knockdown, P < 0.05) confirmed its regulatory capacity. Conclusion: LINC00936 acts as a tumor suppressor in NSCLC via Ras/MAPK pathway modulation, proposing its therapeutic candidacy for precision oncology strategies.

Bray F, Laversanne M, Sung H, et al., 2024, Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 74(3): 229–263.

Chen P, Liu Y, Wen Y, et al., 2022, Non-small Cell Lung Cancer in China. Cancer Communications (London, England), 42(10): 937–970.

Shi Y, Zhao Y, Yang S, et al., 2022, Safety, Efficacy, and Pharmacokinetics of Rezivertinib (BPI-7711) in Patients with Advanced NSCLC With EGFR T790M Mutation: A Phase 1 Dose-escalation and Dose-expansion Study. Journal of Thoracic Oncology: official Publication of the International Association for the Study of Lung Cancer, 17(5): 708–717.

Riely GJ, Wood DE, Ettinger DS, et al., 2024, Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network: JNCCN, 22(4): 249–274.

Ettinger DS, Wood DE, Aisner DL, et al., 2022, Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network: JNCCN, 20(5): 497–530.

Wang M, Herbst RS, Boshoff C, 2021, Toward Personalized Treatment Approaches for Non-small-cell Lung Cancer. Nature Medicine, 27(8): 1345–1356.

Yang SR, Schultheis AM, Yu H, et al., 2022, Precision Medicine in Non-small Cell Lung Cancer: Current Applications and Future Directions. Seminars in Cancer Biology, 84: 184–198.

Mamdani H, Matosevic S, Khalid AB, et al., 2022, Immunotherapy in Lung Cancer: Current Landscape and Future Directions. Frontiers in Immunology, 13: 823618.

Statello L, Guo CJ, Chen LL, et al., 2021, Gene Regulation by Long Non-coding RNAs and Its Biological Functions. Nature Reviews Molecular Cell Biology, 22(2): 96–118.

Zhang XZ, Liu H, Chen SR, 2020, Mechanisms of Long Non-Coding RNAs in Cancers and Their Dynamic Regulations. Cancers, 12(5).

Knoll M, Lodish HF, Sun L, 2015, Long Non-coding RNAs as Regulators of the Endocrine System. Nature Reviews Endocrinology, 11(3): 151–160.

Wang W, Min L, Qiu X, et al., 2021, Biological Function of Long Non-coding RNA (LncRNA) Xist. Frontiers in Cell and Developmental Biology, 9: 645647.

Shaath H, Vishnubalaji R, Elango R, et al., 2022, Long non-coding RNA and RNA-binding Protein Interactions in Cancer: Experimental and Machine Learning Approaches. Seminars in Cancer Biology, 86(Pt 3): 325–345.

Dykes IM, Emanueli C, 2017, Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA. Genomics, Proteomics & Bioinformatics, 15(3): 177–186.

Sun L, Li Y, Yang B, 2016, Downregulated Long Non-coding RNA MEG3 in Breast Cancer Regulates Proliferation, Migration and Invasion by Depending on p53’s Transcriptional Activity. Biochemical and Biophysical Research Communications, 478(1): 323–329.

Fidler-Benaoudia MM, Torre LA, Bray F, et al., 2020, Lung Cancer Incidence in Young Women VS. Young Men: A Systematic Analysis in 40 Countries. International Journal of Cancer, 147(3): 811–819.

Zong S, Dai W, Guo X, et al., 2021, LncRNA-SNHG1 Promotes Macrophage M2-Like Polarization and Contributes to Breast Cancer Growth and Metastasis. Aging, 13(19): 23169–23181.

Zhang C, Wei S, Dai S, et al., 2023, The NR_109/FUBP1/c-Myc Axis Regulates TAM Polarization and Remodels the Tumor Microenvironment to Promote Cancer Development. Journal for Immunotherapy of Cancer, 11(5).

Bach DH, Lee SK, 2018, Long Noncoding RNAs in Cancer Cells. Cancer Letters, 419: 152–166.

Brüggenwirth IMA, Martins PN, 2020, RNA Interference Therapeutics in Organ Transplantation: The Dawn of a New Era. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 20(4): 931–941.

Shrivastava S, Kulkarni P, Thummuri D, et al., 2014, Piperlongumine, an Alkaloid Causes Inhibition of PI3 K/Akt/mTOR Signaling Axis to Induce Caspase-dependent Apoptosis in Human Triple-negative Breast Cancer Cells. Apoptosis: An International Journal on Programmed Cell Death, 19(7): 1148–1164.

Li SY, Zhu Y, Li RN, et al., 2021, LncRNA Lnc-APUE is Repressed by HNF4α and Promotes G1/S Phase Transition and Tumor Growth by Regulating MiR-20b/E2F1 Axis. Advanced Science (Weinheim, Baden-Wurttemberg, Germany), 8(7): 2003094.

Simanshu DK, Nissley DV, McCormick F, 2017, RAS Proteins and Their Regulators in Human Disease. Cell, 170(1): 17–33.

Canon J, Rex K, Saiki AY, et al., 2019, The Clinical KRAS(G12C) Inhibitor AMG 510 Drives Anti-tumour Immunity. Nature, 575(7781): 217–223.

Kinsey CG, Camolotto SA, Boespflug AM, et al., 2019, Publisher Correction: Protective Autophagy Elicited by RAF→MEK→ERK Inhibition Suggests a Treatment Strategy for RAS-driven Cancers. Nature Medicine, 25(5): 861.

Peng SB, Henry JR, Kaufman MD, et al., 2015, Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers. Cancer Cell, 28(3): 384–398.

Kinsey CG, Camolotto SA, Boespflug AM, et al., 2019, Protective Autophagy Elicited by RAF→MEK→ERK Inhibition Suggests a Treatment Strategy for RAS-driven Cancers. Nature Medicine, 25(4): 620–627.

Gonzalez-Magana A, Blanco FJ, 2020, Human PCNA Structure, Function and Interactions. Biomolecules, 10(4).

Mondal S, Adhikari N, Banerjee S, et al., 2020, Matrix Metalloproteinase-9 (MMP-9) and Its Inhibitors in Cancer: A Minireview. European Journal of Medicinal Chemistry, 194: 112260.

Schneider JL, Kurmi K, Dai Y, et al., 2025, GUK1 Activation is a Metabolic Liability in Lung Cancer. Cell, 188(5): 1248–1264.e23.

McFadden DG, Politi K, Bhutkar A, et al., 2016, Mutational landscape of EGFR-, MYC-, and Kras-driven Genetically Engineered Mouse Models of Lung Adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, 113(42): E6409–E6417.

Liu Z, Zhao M, Jiang X, et al., 2022, Upregulation of KLHL17 Promotes the Proliferation and Migration of Non-small Cell Lung Cancer by Activating the Ras/MAPK Signaling Pathway. Laboratory Investigation; a Journal of Technical Methods and Pathology, 102(12): 1389–1399.

Zhang X, Luo Y, Li Q, 2020, TMED3 Promotes Proliferation and Migration in Breast Cancer Cells by Activating Wnt/β-Catenin Signaling. OncoTargets and Therapy, 13: 5819–5830.

Liu XH, Tang DE, Dai Y, et al., 2020, PCNA and GSK3β Interact with Each Other to Regulate H1299 Lung Adenocarcinoma Cells Apoptosis. Neoplasma, 67(1): 15–26.

Park JH, Han HJ, 2009, Caveolin-1 Plays Important Role in EGF-induced Migration and Proliferation of Mouse Embryonic Stem Cells: Involvement of PI3K/Akt and ERK. American Journal of Physiology Cell Physiology, 297(4): C935–C944.

Watanabe M, Miyajima N, Igarashi M, et al., 2009, Sodium Phenylacetate Inhibits the Ras/MAPK Signaling Pathway to Induce Reduction of the c-Raf-1 Protein in Human and Canine Breast Cancer Cells. Breast Cancer Research and Treatment, 118(2): 281–291.