FAM111B在非小细胞肺癌中的研究进展——分子机制、临床意义与基于同源性的功能推演
Research Progress of FAM111B in Non-Small Cell Lung Cancer—Molecular Mechanisms, Clinical Implications, and Homology-Based Functional Deduction
DOI: 10.12677/acm.2026.1651867, PDF,   
作者: 陈云仪, 陈亚娟*：昆明医科大学药学院暨云南省天然药物药理重点实验室(云南省现代生物医药产业学院)，云南 昆明
关键词: FAM111B；非小细胞肺癌；分子机制；预后；FAM111A；FAM111B； Non-Small Cell Lung Cancer； Molecular Mechanism； Prognosis； FAM111A
摘要: 非小细胞肺癌(non-small cell lung cancer, NSCLC)约占全部肺癌病例的85%，其分子异质性与治疗耐药性是影响患者长期生存的主要因素。FAM111B (family with sequence similarity 111 member B)作为含有丝氨酸蛋白酶结构域的蛋白，参与DNA复制应激与细胞周期调控，在多种实体瘤中表达上调且与不良预后密切相关。鉴于FAM111B在肺鳞癌中缺乏系统性研究，且中国人群相关数据匮乏，本文系统梳理了FAM111B在NSCLC中的研究进展，重点综述其在NSCLC中的表达特征、预后意义及分子机制，并结合与同家族成员FAM111A的功能比较推演其潜在致病机制，通过整合现有证据，为后续针对FAM111B的基础研究及临床转化应用提供理论框架。
Abstract: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases, and its molecular heterogeneity and therapeutic resistance represent major factors compromising long-term patient survival. FAM111B (family with sequence similarity 111 member B), a protein harboring a serine protease domain, is involved in the regulation of DNA replication stress and cell cycle progression. It is upregulated in multiple solid tumors and closely associated with poor prognosis. However, systematic studies on FAM111B in lung squamous cell carcinoma remain lacking, particularly data from the Chinese population. This article systematically reviews the research progress of FAM111B in NSCLC, focusing on its expression profile, prognostic value, and molecular mechanisms. By comparing its functions with those of its family member FAM111A, we further deduce its potential oncogenic mechanisms. Through integrating existing evidence, this review aims to provide a theoretical framework for future basic research and clinical translation targeting FAM111B.
文章引用：陈云仪, 陈亚娟. FAM111B在非小细胞肺癌中的研究进展——分子机制、临床意义与基于同源性的功能推演[J]. 临床医学进展, 2026, 16(5): 723-737. https://doi.org/10.12677/acm.2026.1651867

参考文献

[1] Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R.L., Soerjomataram, I., 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, 229-263. [Google Scholar] [CrossRef] [PubMed]
[2] 中华人民共和国国家卫生健康委员会. 原发性肺癌诊疗指南(2022年版) [J]. 中国合理用药探索, 2022, 19(9): 1-28.
[3] Shen, Y., Chen, J. and Li, X. (2025) Differences between Lung Adenocarcinoma and Lung Squamous Cell Carcinoma: Driver Genes, Therapeutic Targets, and Clinical Efficacy. Genes & Diseases, 12, Article ID: 101374. [Google Scholar] [CrossRef] [PubMed]
[4] Nu er lan, S.T.E., Yu, B., Yang, Y., Shen, Y., Xu, B., Zhan, Y., et al. (2024) Discover Mutational Differences between Lung Adenocarcinoma and Lung Squamous Cell Carcinoma and Search for More Effective Biomarkers for Immunotherapy. Cancer Management and Research, 16, 1759-1773. [Google Scholar] [CrossRef] [PubMed]
[5] Tong, Y., Wang, Y., Chen, Y., Fan, Y. and Li, H. (2025) Decoding the Tumor Immune Microenvironment in Lung Squamous Cell Carcinoma: Characteristics, Regulatory Mechanisms, and Future Directions in Immunotherapy. Translational Lung Cancer Research, 14, 4112-4130. [Google Scholar] [CrossRef] 
[6] 李廷慧, 刘芳, 任志鹏, 等. 肺鳞状细胞癌和腺癌PD-L1蛋白及相关miRNA表达差异的研究[J]. 现代生物医学进展, 2022, 22(13): 2495-2498.
[7] Schiller, J.H., Harrington, D., Belani, C.P., Langer, C., Sandler, A., Krook, J., et al. (2002) Comparison of Four Chemotherapy Regimens for Advanced Non-Small-Cell Lung Cancer. New England Journal of Medicine, 346, 92-98. [Google Scholar] [CrossRef] [PubMed]
[8] Wolf, J., Helland, Å., Oh, I.J., Migliorino, M.R., Dziadziuszko, R., Wrona, A., et al. (2022) Final Efficacy and Safety Data, and Exploratory Molecular Profiling from the Phase III ALUR Study of Alectinib versus Chemotherapy in Crizotinib-Pretreated ALK-Positive Non-Small-Cell Lung Cancer. ESMO Open, 7, Article ID: 100333. [Google Scholar] [CrossRef] [PubMed]
[9] Soria, J., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K.H., et al. (2018) Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. New England Journal of Medicine, 378, 113-125. [Google Scholar] [CrossRef] [PubMed]
[10] Lu, S., Kato, T., Dong, X., Ahn, M., Quang, L., Soparattanapaisarn, N., et al. (2024) Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. New England Journal of Medicine, 391, 585-597. [Google Scholar] [CrossRef] [PubMed]
[11] Chen, S., Wang, Z. and Sun, B. (2025) Chinese Society of Clinical Oncology Non-Small Cell Lung Cancer (CSCO NSCLC) Guidelines in 2024: Key Update on the Management of Early and Locally Advanced NSCLC. Cancer Biology & Medicine. [Google Scholar] [CrossRef] [PubMed]
[12] Dong, X., Jian, H., Huang, M., Yuan, S., Zhu, Z., Wu, L., et al. (2024) 1248P Osimertinib (OSI) after Definitive Chemoradiotherapy (CRT) in Unresectable Stage III Epidermal Growth Factor Receptor-Mutated (EGFRm) NSCLC: LAURA China Cohort Analysis. Annals of Oncology, 35, S799. [Google Scholar] [CrossRef] 
[13] Reck, M., Rodríguez-Abreu, D., Robinson, A.G., Hui, R., Csőszi, T., Fülöp, A., et al. (2016) Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. New England Journal of Medicine, 375, 1823-1833. [Google Scholar] [CrossRef] [PubMed]
[14] Forde, P.M., Spicer, J., Lu, S., Provencio, M., Mitsudomi, T., Awad, M.M., et al. (2022) Neoadjuvant Nivolumab Plus Chemotherapy in Resectable Lung Cancer. New England Journal of Medicine, 386, 1973-1985. [Google Scholar] [CrossRef] [PubMed]
[15] 段毅, 杨青承, 施远龙, 等. PD-1/PD-L1抑制剂联合新型治疗在晚期非小细胞肺癌中的临床研究进展[J/OL]. 中国全科医学: 1-8.
https://link.cnki.net/urlid/13.1222.R.20250425.1028.012, 2026-03-28.
[16] Yu, H.A., Arcila, M.E., Rekhtman, N., Sima, C.S., Zakowski, M.F., Pao, W., et al. (2013) Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers. Clinical Cancer Research, 19, 2240-2247. [Google Scholar] [CrossRef] [PubMed]
[17] Engelman, J.A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J.O., et al. (2007) MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling. Science, 316, 1039-1043. [Google Scholar] [CrossRef] [PubMed]
[18] Sequist, L.V., Waltman, B.A., Dias-Santagata, D., Digumarthy, S., Turke, A.B., Fidias, P., et al. (2011) Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. Science Translational Medicine, 3, 75ra26. [Google Scholar] [CrossRef] [PubMed]
[19] Sharma, P., Hu-Lieskovan, S., Wargo, J.A. and Ribas, A. (2017) Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell, 168, 707-723. [Google Scholar] [CrossRef] [PubMed]
[20] Gao, J., Shi, L.Z., Zhao, H., Chen, J., Xiong, L., He, Q., et al. (2016) Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy. Cell, 167, 397-404.e9. [Google Scholar] [CrossRef] [PubMed]
[21] Zaretsky, J.M., Garcia-Diaz, A., Shin, D.S., Escuin-Ordinas, H., Hugo, W., Hu-Lieskovan, S., et al. (2016) Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. New England Journal of Medicine, 375, 819-829. [Google Scholar] [CrossRef] [PubMed]
[22] Tumeh, P.C., Harview, C.L., Yearley, J.H., Shintaku, I.P., Taylor, E.J.M., Robert, L., et al. (2014) PD-1 Blockade Induces Responses by Inhibiting Adaptive Immune Resistance. Nature, 515, 568-571. [Google Scholar] [CrossRef] [PubMed]
[23] Chen, F., Zheng, L., Li, Y., Li, H., Yao, Z. and Li, M. (2019) Mutation in FAM111B Causes Hereditary Fibrosing Poikiloderma with Tendon Contracture, Myopathy, and Pulmonary Fibrosis. Acta Dermato Venereologica, 99, 695-696. [Google Scholar] [CrossRef] [PubMed]
[24] Arowolo, A., Malebana, M., Sunda, F. and Rhoda, C. (2022) Proposed Cellular Function of the Human FAM111B Protein and Dysregulation in Fibrosis and Cancer. Frontiers in Oncology, 12, Article 932167. [Google Scholar] [CrossRef] [PubMed]
[25] Wu, H. and Liang, C. (2023) Pan-Cancer Analysis of the Tumorigenic Effect and Prognostic Diagnostic Value of FAM111B in Human Carcinomas. International Journal of General Medicine, 16, 1845-1865. [Google Scholar] [CrossRef] [PubMed]
[26] Welter, A.L. and Machida, Y.J. (2022) Functions and Evolution of FAM111 Serine Proteases. Frontiers in Molecular Biosciences, 9, Article 1081166. [Google Scholar] [CrossRef] [PubMed]
[27] Kliszczak, M., Moralli, D., Jankowska, J.D., Bryjka, P., Subha Meem, L., Goncalves, T., et al. (2023) Loss of FAM111B Protease Mutated in Hereditary Fibrosing Poikiloderma Negatively Regulates Telomere Length. Frontiers in Cell and Developmental Biology, 11, Article 1175069. [Google Scholar] [CrossRef] [PubMed]
[28] Naicker, D., Rhoda, C., Sunda, F. and Arowolo, A. (2024) Unravelling the Intricate Roles of FAM111A and FAM111B: From Protease-Mediated Cellular Processes to Disease Implications. International Journal of Molecular Sciences, 25, Article 2845. [Google Scholar] [CrossRef] [PubMed]
[29] Uhlén, M., Fagerberg, L., Hallström, B.M., Lindskog, C., Oksvold, P., Mardinoglu, A., et al. (2015) Tissue-Based Map of the Human Proteome. Science, 347, Article ID: 1260419. [Google Scholar] [CrossRef] [PubMed]
[30] Kawasaki, K., Nojima, S., Hijiki, S., Tahara, S., Ohshima, K., Matsui, T., et al. (2020) FAM111B Enhances Proliferation of KRAS‐Driven Lung Adenocarcinoma by Degrading P16. Cancer Science, 111, 2635-2646. [Google Scholar] [CrossRef] [PubMed]
[31] Sun, H., Liu, K., Huang, J., Sun, Q., Shao, C., Luo, J., et al. (2019) Fam111b, a Direct Target of P53, Promotes the Malignant Process of Lung Adenocarcinoma. OncoTargets and Therapy, 12, 2829-2842. [Google Scholar] [CrossRef] [PubMed]
[32] Kojima, Y., Machida, Y., Palani, S., Caulfield, T.R., Radisky, E.S., Kaufmann, S.H., et al. (2020) FAM111A Protects Replication Forks from Protein Obstacles via Its Trypsin-Like Domain. Nature Communications, 11, Article No. 1318. [Google Scholar] [CrossRef] [PubMed]
[33] Nie, M., Oravcová, M., Jami‐Alahmadi, Y., Wohlschlegel, J.A., Lazzerini‐Denchi, E. and Boddy, M.N. (2021) FAM111A Induces Nuclear Dysfunction in Disease and Viral Restriction. EMBO reports, 22, e50803. [Google Scholar] [CrossRef] [PubMed]
[34] Palani, S., Machida, Y., Alvey, J.R., Mishra, V., Welter, A.L., Cui, G., et al. (2024) Dimerization-Dependent Serine Protease Activity of FAM111A Prevents Replication Fork Stalling at Topoisomerase 1 Cleavage Complexes. Nature Communications, 15, Article No. 2064. [Google Scholar] [CrossRef] [PubMed]
[35] Hoffmann, S., Pentakota, S., Mund, A., Haahr, P., Coscia, F., Gallo, M., et al. (2020) FAM111 Protease Activity Undermines Cellular Fitness and Is Amplified by Gain‐of‐Function Mutations in Human Disease. EMBO reports, 21, e50662. [Google Scholar] [CrossRef] [PubMed]
[36] Human Protein Atlas (2026) FAM111B in Lung Squamous Cell Carcinoma.
https://v18.proteinatlas.org/ENSG00000189057-FAM111B/pathology/tissue/lung+cancer/LUSC
[37] Wei, H., Wang, H., Wang, G., Qu, L., Jiang, L., Dai, S., et al. (2023) Structures of p53/BCL-2 Complex Suggest a Mechanism for P53 to Antagonize BCL-2 Activity. Nature Communications, 14, Article No. 4300. [Google Scholar] [CrossRef] [PubMed]
[38] Li, W., Wei, F., Zhou, T., Feng, L. and Zhang, L. (2025) FAM111B Overexpression and Immune Cell Infiltration: Implications for Ovarian Cancer Immunotherapy. Biomedicines, 13, Article 1295. [Google Scholar] [CrossRef] [PubMed]
[39] Li, C., Jiang, P., Wei, S., Xu, X. and Wang, J. (2020) Regulatory T Cells in Tumor Microenvironment: New Mechanisms, Potential Therapeutic Strategies and Future Prospects. Molecular Cancer, 19, Article No. 116. [Google Scholar] [CrossRef] [PubMed]
[40] So, L., Obata-Ninomiya, K., Hu, A., Muir, V.S., Takamori, A., Song, J., et al. (2023) Regulatory T Cells Suppress CD4+ Effector T Cell Activation by Controlling Protein Synthesis. Journal of Experimental Medicine, 220, e20221676. [Google Scholar] [CrossRef] [PubMed]
[41] Marangoni, F., Zhakyp, A., Corsini, M., Geels, S.N., Carrizosa, E., Thelen, M., et al. (2021) Expansion of Tumor-Associated Treg Cells Upon Disruption of a CTLA-4-Dependent Feedback Loop. Cell, 184, 3998-4015.e19. [Google Scholar] [CrossRef] [PubMed]
[42] Li, W., Feng, S., Wu, H., Deng, J., Zhou, W., Jia, M., et al. (2022) Comprehensive Analysis of CDK1-Associated Cerna Network Revealing the Key Pathways LINC00460/LINC00525-Hsa-Mir-338-FAM111/ZWINT as Prognostic Biomarkers in Lung Adenocarcinoma Combined with Experiments. Cells, 11, Article 1220. [Google Scholar] [CrossRef] [PubMed]
[43] Li, W., Hu, S., Han, Z. and Jiang, X. (2022) YY1-Induced Transcriptional Activation of FAM111B Contributes to the Malignancy of Breast Cancer. Clinical Breast Cancer, 22, e417-e425. [Google Scholar] [CrossRef] [PubMed]
[44] Liu, X., Yi, J., Li, T., Wen, J., Huang, K., Liu, J., et al. (2024) DRMref: Comprehensive Reference Map of Drug Resistance Mechanisms in Human Cancer. Nucleic Acids Research, 52, D1253-D1264. [Google Scholar] [CrossRef] [PubMed]
[45] Wei, F., Li, W., Zhou, T., Yuan, X. and Zhang, L. (2025) Unveiling FAM111B: A Pan-Cancer Biomarker for DNA Repair and Immune Infiltration. International Journal of Molecular Sciences, 26, Article 3151. [Google Scholar] [CrossRef] [PubMed]
[46] Frías, C., García-Aranda, C., De Juan, C., Morán, A., Ortega, P., Gómez, A., et al. (2008) Telomere Shortening Is Associated with Poor Prognosis and Telomerase Activity Correlates with DNA Repair Impairment in Non-Small Cell Lung Cancer. Lung Cancer, 60, 416-425. [Google Scholar] [CrossRef] [PubMed]
[47] Faugeras, E., Véronèse, L., Jeannin, G., Janicot, H., Bailly, S., Bay, J., et al. (2022) Telomere Status of Advanced Non-Small-Cell Lung Cancer Offers a Novel Promising Prognostic and Predictive Biomarker. Cancers, 15, Article 290. [Google Scholar] [CrossRef] [PubMed]
[48] Yan, Y., Shao, L., Meng, G., Pan, G., Li, R., Xiong, C., et al. (2025) Targeting FAM111B Attenuates Mitophagy and Increases the Sensitivity to Lenvatinib Treatment by Increasing MFN2 Stability in Hepatocellular Carcinoma. Cell Death & Disease, 16, Article No. 645. [Google Scholar] [CrossRef] [PubMed]
[49] Wang, H., Wang, H., Chen, J., Liu, P. and Xiao, X. (2024) Overexpressed FAM111B Degrades GSDMA to Promote Esophageal Cancer Tumorigenesis and Cisplatin Resistance. Cellular Oncology, 47, 343-359. [Google Scholar] [CrossRef] [PubMed]

为你推荐