Aberrant nuclear lamina contributes to the malignancy of human gliomas

Shunqi Pei; Xuehui Wang; Xuan Wang; Hao Huang; Huaping Tao; Binghua Xie; Aifen Yang; Mengsheng Qiu; Zhou Tan

doi:10.1016/j.jgg.2021.08.013

Volume 49 Issue 2

Mar. 2022

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Article Navigation > Journal of Genetics and Genomics > 2022 > 49(2): 132-144

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Aberrant nuclear lamina contributes to the malignancy of human gliomas

doi: 10.1016/j.jgg.2021.08.013

Institute of Life Sciences, Key Laboratory of Organ Development and Regeneration of Zhejiang Province, College of Life Sciences, Hangzhou Normal University, Zhejiang 311121, China

Funds:

This work was supported by grants from High-level students returning to China (team) project in Hangzhou (2017), Zhejiang Provincial Natural Science Foundation of China (LY19C090002, LQ18C090005), Hangzhou Agriculture and Social Development Project (20191203B20).

Received Date: 2021-03-30
Accepted Date: 2021-08-13
Rev Recd Date: 2021-08-05
Publish Date: 2021-09-13

Abstract

Abstract

Glioma is the most common type of tumor in the central nervous system, accounting for around 80% of all malignant brain tumors. Previous studies showed a significant association between nuclear morphology and the malignant progress of gliomas. By virtue of integrated proteomics and genomics analyses as well as experimental validations, we identify three nuclear lamin genes (LMNA, LMNB1, and LMNB2) that are significantly upregulated in glioma tissues compared with normal brain tissues. We show that elevated expressions of LMNB1, LMNB2, and LMNA in glioma cells are highly associated with the rapid progression of the disease and the knockdown of LMNB1, LMNB2, and LMNA dramatically suppresses glioma progression in both in vitro and in vivo mouse models. Moreover, the repression of glioma cell growth by lamin knockdown is mediated by the pRb-mediated G1-S inhibition. On the contrary, overexpression of lamins in normal human astrocytes dramatically induced nuclear morphological aberrations and accelerated cell growth. Together, our multi-omics-based analysis has revealed a previously unrecognized role of lamin genes in gliomagenesis, providing a strong support for the key link between aberrant tumor nuclear shape and the survival of glioma patients. Based on these findings, lamins are proposed to be potential oncogene targets for therapeutic treatments of brain tumors.
- Gliomas,
- Proteomics,
- Genomics,
- Nucleus,
- Lamins,
- Malignancy

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References(49)

References

Alaiya, A.A., Franzen, B., Fujioka, K., Moberger, B., Schedvins, K., Silfversvard, C., Linder, S.,Auer, G., 1997. Phenotypic analysis of ovarian carcinoma:polypeptide expression in benign, borderline and malignant tumors. Int. J. Cancer 73, 678-683

Bell, E.S.,Lammerding, J., 2016. Causes and consequences of nuclear envelope alterations in tumour progression. Eur. J. Cell Biol. 95, 449-464

Belt, E.J., Fijneman, R.J., van den Berg, E.G., Bril, H., Delis-van Diemen, P.M., Tijssen, M., van Essen, H.F., de Lange-de Klerk, E.S., Belien, J.A., Stockmann, H.B., et al., 2011. Loss of lamin A/C expression in stage II and III colon cancer is associated with disease recurrence. Eur. J. Cancer 47, 1837-1845

Boruah, D.,Deb, P., 2013. Utility of nuclear morphometry in predicting grades of diffusely infiltrating gliomas. ISRN Oncol. 2013, 760653

Capo-chichi, C.D., Cai, K.Q., Smedberg, J., Ganjei-Azar, P., Godwin, A.K.,Xu, X.X., 2011. Loss of A-type lamin expression compromises nuclear envelope integrity in breast cancer. Chin. J. Cancer 30, 415-425

Cerami, E., Gao, J., Dogrusoz, U., Gross, B.E., Sumer, S.O., Aksoy, B.A., Jacobsen, A., Byrne, C.J., Heuer, M.L., Larsson, E., et al., 2012. The cBio cancer genomics portal:an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401-404

Chen, Y., Mo, L., Wang, X., Chen, B., Hua, Y., Gong, L., Yang, F., Li, Y., Chen, F., Zhu, G., et al., 2020. TPGS-1000 exhibits potent anticancer activity for hepatocellular carcinoma in vitro and in vivo. Aging 12, 1624-1642

Coffinier, C., Jung, H.J., Nobumori, C., Chang, S., Tu, Y., Barnes, R.H., 2nd, Yoshinaga, Y., de Jong, P.J., Vergnes, L., Reue, K., et al., 2011. Deficiencies in lamin B1 and lamin B2 cause neurodevelopmental defects and distinct nuclear shape abnormalities in neurons. Mol. Bio. Cell 22, 4683-4693

Cohen, A.L.,Colman, H., 2015. Glioma biology and molecular markers. Cancer Treat. Res. 163, 15-30

Davidson, P.M.,Lammerding, J., 2014. Broken nuclei——lamins, nuclear mechanics, and disease. Trends Cell Biol. 24, 247-256

Diaz, G., Zuccarelli, A., Pelligra, I.,Ghiani, A., 1989. Elliptic fourier analysis of cell and nuclear shapes. Comp. Biomed. Res. Int. J. 22, 405-414

Dolecek, T.A., Propp, J.M., Stroup, N.E.,Kruchko, C., 2012. CBTRUS statistical report:primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol. 14 Suppl. 5, v1-49

Fahraeus, R., Paramio, J.M., Ball, K.L., Lain, S.,Lane, D.P., 1996. Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A. Curr. Biol.:CB. 6, 84-91

Friedl, P., Wolf, K.,Lammerding, J., 2011. Nuclear mechanics during cell migration. Curr. Opin. Cell Biol. 23, 55-64

Gao, G.F., Parker, J.S., Reynolds, S.M., Silva, T.C., Wang, L.-B., Zhou, W., Akbani, R., Bailey, M., Balu, S., Berman, B.P., et al., 2019. Before and after:comparison of legacy and harmonized TCGA genomic data commons' data. Cell Syst. 9, 24-34 e10

Garvalov, B.K., Muhammad, S.,Dobreva, G., 2019. Lamin B1 in cancer and aging. Aging 11, 7336-7338

Gruenbaum, Y.,Foisner, R., 2015. Lamins:nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. Annu. Rev. Biochem. 84, 131-164

Hanif, F., Muzaffar, K., Perveen, K., Malhi, S.M.,Simjee Sh, U., 2017. Glioblastoma multiforme:a review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac. J. Cancer Prev.:APJCP. 18, 3-9

Harada, T., Swift, J., Irianto, J., Shin, J.W., Spinler, K.R., Athirasala, A., Diegmiller, R., Dingal, P.C., Ivanovska, I.L.,Discher, D.E., 2014. Nuclear lamin stiffness is a barrier to 3D migration, but softness can limit survival. J. Cell Biol. 204, 669-682

Ho, C.Y.,Lammerding, J., 2012. Lamins at a glance. J. Cell Sci. 125, 2087-2093

Huang da, W., Sherman, B.T.,Lempicki, R.A., 2009. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44-57

Irianto, J., Pfeifer, C.R., Ivanovska, I.L., Swift, J.,Discher, D.E., 2016. Nuclear lamins in cancer. Cell. Mol. Bioeng. 9, 258-267

Jooma, R., Waqas, M.,Khan, I., 2019. Diffuse low-grade glioma-changing concepts in diagnosis and management:a review. Asian J. Neurosurg. 14, 356-363

Kong, L., Schafer, G., Bu, H., Zhang, Y., Zhang, Y.,Klocker, H., 2012. Lamin A/C protein is overexpressed in tissue-invading prostate cancer and promotes prostate cancer cell growth, migration and invasion through the PI3K/AKT/PTEN pathway. Carcinogenesis 33, 751-759

Lammerding, J., Schulze, P.C., Takahashi, T., Kozlov, S., Sullivan, T., Kamm, R.D., Stewart, C.L.,Lee, R.T., 2004. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J. Clin. Invest. 113, 370-378

Leman, E.S.,Getzenberg, R.H., 2002. Nuclear matrix proteins as biomarkers in prostate cancer. J. Cell. Biochem. 86, 213-223

Louis, D.N., Perry, A., Reifenberger, G., von Deimling, A., Figarella-Branger, D., Cavenee, W.K., Ohgaki, H., Wiestler, O.D., Kleihues, P.,Ellison, D.W., 2016. The 2016 World Health organization classification of tumors of the central nervous system:a summary. Acta Neuropathol. 131, 803-820

Mejat, A., Decostre, V., Li, J., Renou, L., Kesari, A., Hantai, D., Stewart, C.L., Xiao, X., Hoffman, E., Bonne, G., et al., 2009. Lamin A/C-mediated neuromuscular junction defects in Emery-Dreifuss muscular dystrophy. J. Cell Biol. 184, 31-44

Nafe, R., Franz, K., Schlote, W.,Schneider, B., 2005. Morphology of tumor cell nuclei is significantly related with survival time of patients with glioblastomas. Clin. Cancer Res. 11, 2141-2148

Nafe, R., Franz, K., Schlote, W.,Schneider, B., 2006. The morphology of perinecrotic tumor cell nuclei in glioblastomas shows a significant relationship with survival time. Oncol. Rep. 16, 555-562

Nizamutdinov, D., Stock, E.M., Dandashi, J.A., Vasquez, E.A., Mao, Y., Dayawansa, S., Zhang, J., Wu, E., Fonkem, E.,Huang, J.H., 2018. Prognostication of survival outcomes in patients diagnosed with glioblastoma. World Neurosurg. 109, e67-e74

Omuro, A.,DeAngelis, L.M., 2013. Glioblastoma and other malignant gliomas:a clinical review. JAMA. 310, 1842-1850

Shannon, P., Markiel, A., Ozier, O., Baliga, N.S., Wang, J.T., Ramage, D., Amin, N., Schwikowski, B.,Ideker, T., 2003. Cytoscape:a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498-2504

Shen, Y., Wang, X., Guo, S., Qiu, M., Hou, G.,Tan, Z., 2020. Evolutionary genomics analysis of human nucleus-encoded mitochondrial genes:implications for the roles of energy production and metabolic pathways in the pathogenesis and pathophysiology of demyelinating diseases. Neurosci. Lett. 715, 134600

Skinner, B.M.,Johnson, E.E., 2017. Nuclear morphologies:their diversity and functional relevance. Chromosoma 126, 195-212

Stadelmann, B., Khandjian, E., Hirt, A., Luthy, A., Weil, R.,Wagner, H.P., 1990. Repression of nuclear lamin A and C gene expression in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells. Leuk. Res. 14, 815-821

Subramanian, A., Tamayo, P., Mootha, V.K., Mukherjee, S., Ebert, B.L., Gillette, M.A., Paulovich, A., Pomeroy, S.L., Golub, T.R., Lander, E.S., et al., 2005. Gene set enrichment analysis:a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. U. S. A. 102, 15545-15550

Sun, S., Xu, M.Z., Poon, R.T., Day, P.J.,Luk, J.M., 2010. Circulating Lamin B1 (LMNB1) biomarker detects early stages of liver cancer in patients. J. Proteome Res. 9, 70-78

Tan, Z., Li, J., Zhang, X., Yang, X., Zhang, Z., Yin, K.J.,Huang, H., 2018. P53 promotes retinoid acid-induced smooth muscle cell differentiation by targeting myocardin. Stem Cell. Dev. 27, 534-544

Tilli, C.M., Ramaekers, F.C., Broers, J.L., Hutchison, C.J.,Neumann, H.A., 2003. Lamin expression in normal human skin, actinic keratosis, squamous cell carcinoma and basal cell carcinoma. Br. J. Dermatol. 148, 102-109

Utsuno, H., Miyamoto, T., Oka, K.,Shiozawa, T., 2014. Morphological alterations in protamine-deficient spermatozoa. Hum. Reprod. 29, 2374-2381

Warde-Farley, D., Donaldson, S.L., Comes, O., Zuberi, K., Badrawi, R., Chao, P., Franz, M., Grouios, C., Kazi, F., Lopes, C.T., et al., 2010. The GeneMANIA prediction server:biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 38, W214-W220

Webster, M., Witkin, K.L.,Cohen-Fix, O., 2009. Sizing up the nucleus:nuclear shape, size and nuclear-envelope assembly. J. Cell Sci. 122, 1477-1486

Wilson, K.L., Zastrow, M.S.,Lee, K.K., 2001. Lamins and disease:insights into nuclear infrastructure. Cell 104, 647-650

Witthayanuwat, S., Pesee, M., Supaadirek, C., Supakalin, N., Thamronganantasakul, K.,Krusun, S., 2018. Survival analysis of glioblastoma multiforme. Asian Pac. J. Cancer Prev.:APJCP. 19, 2613-2617

Wu, Z., Wu, L., Weng, D., Xu, D., Geng, J.,Zhao, F., 2009. Reduced expression of lamin A/C correlates with poor histological differentiation and prognosis in primary gastric carcinoma. J. Exp. Clin. Cancer Res.:CR. 28, 8

Xu, D., Liu, A., Wang, X., Chen, Y., Shen, Y., Tan, Z.,Qiu, M., 2018a. Repression of Septin9 and Septin2 suppresses tumor growth of human glioblastoma cells. Cell Death Dis. 9, 514

Xu, D., Liu, A., Wang, X., Zhang, M., Zhang, Z., Tan, Z.,Qiu, M., 2018b. Identifying suitable reference genes for developing and injured mouse CNS tissues. Dev. Neurobiol. 78, 39-50

Zink, D., Fischer, A.H.,Nickerson, J.A., 2004. Nuclear structure in cancer cells. Nat. Rev. Cancer 4, 677-687

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