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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Research Article

Knockdown of LRCH4 Remodels Tumor Microenvironment Through Inhibiting YAP and TGF-β/Smad Signaling Pathway in Colorectal Cancer

Author(s): Zhiwen Li, Zhenhua Cui, Xianren Wang and Yanfeng Lv*

Volume 27, Issue 12, 2024

Published on: 20 November, 2023

Page: [1823 - 1829] Pages: 7

DOI: 10.2174/0113862073267943231101065948

Price: $65

Abstract

Background: Colorectal cancer is one of the most common gastrointestinal malignancies worldwide. LRCH4 is the top 1 gene associated with an unfavorable prognosis in colorectal cancer.

Methods: Here, we reported that the knockdown of LRCH4 inhibited the proliferation, migration and invasion in HT29 cells.

Results: The activity of Yes-Associated Protein (YAP), a transcription factor in the Hppo-YAP signaling pathway, was significantly inhibited by LRCH4-siRNA. LRCH4 knockdown also reversed the EMT and regulated the expression of extracellular matrix (ECM) protein, Fibronectin and Collagen IV in HT29 cells. In addition, the TGF-β/Smad signaling pathway, as the downstream pathway of Yap, was also inhibited by LRCH4 knockdown.

Conclusion: Knockdown of LRCH4 involved in the regulation of ECM and EMT and inhibited YAP and the TGF-β/Smad signaling pathway in colorectal cancer cells. Our study provided a mechanism of LRCH4 on colorectal cancer cells, and a new potential target for clinical tumor treatment.

Keywords: Colorectal cancer, prognosis, tumor microenvironment, YAP, epithelial mesenchymal transformation, calponin homology (CH).

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[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[3]
Rivière, T.; Bader, A.; Pogoda, K.; Walzog, B.; Maier-Begandt, D. Structure and emerging functions of LRCH proteins in leukocyte biology. Front. Cell Dev. Biol., 2020, 8, 584134.
[http://dx.doi.org/10.3389/fcell.2020.584134] [PMID: 33072765]
[4]
Uhlen, M.; Zhang, C.; Lee, S.; Sjöstedt, E.; Fagerberg, L.; Bidkhori, G.; Benfeitas, R.; Arif, M.; Liu, Z.; Edfors, F.; Sanli, K.; von Feilitzen, K.; Oksvold, P.; Lundberg, E.; Hober, S.; Nilsson, P.; Mattsson, J.; Schwenk, J.M.; Brunnström, H.; Glimelius, B.; Sjöblom, T.; Edqvist, P.H.; Djureinovic, D.; Micke, P.; Lindskog, C.; Mardinoglu, A.; Ponten, F. A pathology atlas of the human cancer transcriptome. Science, 2017, 357(6352), eaan2507.
[http://dx.doi.org/10.1126/science.aan2507] [PMID: 28818916]
[5]
Foussard, H.; Ferrer, P.; Valenti, P.; Polesello, C.; Carreno, S.; Payre, F. LRCH proteins: A novel family of cytoskeletal regulators. PLoS One, 2010, 5(8), e12257.
[http://dx.doi.org/10.1371/journal.pone.0012257] [PMID: 20805893]
[6]
Aloor, J.J.; Azzam, K.M.; Guardiola, J.J.; Gowdy, K.M.; Madenspacher, J.H.; Gabor, K.A.; Mueller, G.A.; Lin, W.C.; Lowe, J.M.; Gruzdev, A.; Henderson, M.W.; Draper, D.W.; Merrick, B.A.; Fessler, M.B. Leucine-rich repeats and calponin homology containing 4 (Lrch4) regulates the innate immune response. J. Biol. Chem., 2019, 294(6), 1997-2008.
[http://dx.doi.org/10.1074/jbc.RA118.004300] [PMID: 30523158]
[7]
Hong, M.G.; Myers, A.J.; Magnusson, P.K.E.; Prince, J.A. Transcriptome-wide assessment of human brain and lymphocyte senescence. PLoS One, 2008, 3(8), e3024.
[http://dx.doi.org/10.1371/journal.pone.0003024] [PMID: 18714388]
[8]
Huo, T.; Canepa, R.; Sura, A.; Modave, F.; Gong, Y. Colorectal cancer stages transcriptome analysis. PLoS One, 2017, 12(11), e0188697.
[http://dx.doi.org/10.1371/journal.pone.0188697] [PMID: 29182684]
[9]
Palani, S.; Ghosh, S.; Ivorra-Molla, E.; Clarke, S.; Suchenko, A.; Balasubramanian, M.K.; Köster, D.V. Calponin-homology domain mediated bending of membrane-associated actin filaments. eLife, 2021, 10, e61078.
[http://dx.doi.org/10.7554/eLife.61078] [PMID: 34269679]
[10]
Aharonov, A.; Shakked, A.; Umansky, K.B.; Savidor, A.; Genzelinakh, A.; Kain, D.; Lendengolts, D.; Revach, O.Y.; Morikawa, Y.; Dong, J.; Levin, Y.; Geiger, B.; Martin, J.F.; Tzahor, E. ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration. Nat. Cell Biol., 2020, 22(11), 1346-1356.
[http://dx.doi.org/10.1038/s41556-020-00588-4] [PMID: 33046882]
[11]
Liu, L.; Liu, M.; Xie, D.; Liu, X.; Yan, H. Role of the extracellular matrix and YAP/TAZ in cell reprogramming. Differentiation, 2021, 122, 1-6.
[12]
Babaei, G.; Aziz, S.; Jaghi, N. EMT, cancer stem cells and autophagy; The three main axes of metastasis. Biomed. Pharmacother., 2021, 133, 110909.
[13]
Graziani, V.; Rodriguez-Hernandez, I.; Maiques, O.; Sanz-Moreno, V. The amoeboid state as part of the epithelial-to-mesenchymal transition programme. Trends Cell Biol., 2022, 32(3), 228-242.
[http://dx.doi.org/10.1016/j.tcb.2021.10.004] [PMID: 34836782]
[14]
Khalaf, K.; Hana, D.; Chou, J.T.T.; Singh, C.; Mackiewicz, A.; Kaczmarek, M. Aspects of the tumor microenvironment involved in immune resistance and drug resistance. Front. Immunol., 2021, 12, 656364.
[http://dx.doi.org/10.3389/fimmu.2021.656364] [PMID: 34122412]
[15]
Wu, J.; Strawn, T.L.; Luo, M.; Wang, L.; Li, R.; Ren, M.; Xia, J.; Zhang, Z.; Ma, W.; Luo, T.; Lawrence, D.A.; Fay, W.P. Plasminogen activator inhibitor-1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor-2-αVβ3 integrin cross talk. Arterioscler. Thromb. Vasc. Biol., 2015, 35(1), 111-120.
[http://dx.doi.org/10.1161/ATVBAHA.114.304554] [PMID: 25378411]
[16]
Modi, S.J.; Kulkarni, V.M. Discovery of VEGFR-2 inhibitors exerting significant anticancer activity against CD44+ and CD133+ cancer stem cells (CSCs): Reversal of TGF-β induced epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma. Eur. J. Med. Chem., 2020, 207, 112851.
[http://dx.doi.org/10.1016/j.ejmech.2020.112851] [PMID: 33002846]
[17]
Nicaise, A.M.; Johnson, K.M.; Willis, C.M.; Guzzo, R.M.; Crocker, S.J. TIMP-1 promotes oligodendrocyte differentiation through receptor-mediated signaling. Mol. Neurobiol., 2019, 56(5), 3380-3392.
[http://dx.doi.org/10.1007/s12035-018-1310-7] [PMID: 30121936]
[18]
McMahon, B.; Kwaan, H.C. The plasminogen activator system and cancer. Pathophysiol. Haemost. Thromb., 2007, 36(3-4), 184-194.
[http://dx.doi.org/10.1159/000175156] [PMID: 19176991]
[19]
Peng, D.; Fu, M.; Wang, M.; Wei, Y.; Wei, X. Targeting TGF-β signal transduction for fibrosis and cancer therapy. Mol. Cancer, 2022, 21(1), 104.
[http://dx.doi.org/10.1186/s12943-022-01569-x] [PMID: 35461253]
[20]
An, Y.; Ren, Y.; Wang, J.; Zang, J.; Gao, M.; Wang, H.; Wang, S.; Dong, Y. MST1/2 in PDGFRα + cells negatively regulates TGF-β-induced myofibroblast accumulation in renal fibrosis. Am. J. Physiol. Renal Physiol., 2022, 322(5), F512-F526.
[http://dx.doi.org/10.1152/ajprenal.00367.2021] [PMID: 35253468]
[21]
Zhang, T.; He, X.; Caldwell, L.; Goru, S.K.; Ulloa Severino, L.; Tolosa, M.F.; Misra, P.S.; McEvoy, C.M.; Christova, T.; Liu, Y.; Atin, C.; Zhang, J.; Hu, C.; Vukosa, N.; Chen, X.; Krizova, A.; Kirpalani, A.; Gregorieff, A.; Ni, R.; Chan, K.; Gill, M.K.; Attisano, L.; Wrana, J.L.; Yuen, D.A. NUAK1 promotes organ fibrosis via YAP and TGF-β/SMAD signaling. Sci. Transl. Med., 2022, 14(637), eaaz4028.
[http://dx.doi.org/10.1126/scitranslmed.aaz4028] [PMID: 35320001]
[22]
Nakamura, R.; Hiwatashi, N.; Bing, R.; Doyle, C.P.; Branski, R.C. Concurrent YAP/TAZ and SMAD signaling mediate vocal fold fibrosis. Sci. Rep., 2021, 11(1), 13484.
[http://dx.doi.org/10.1038/s41598-021-92871-z] [PMID: 34188130]
[23]
Wang, D.; Lin, L.; Lei, K.; Zeng, J.; Luo, J.; Yin, Y.; Li, Y.; Zhang, L.; Nie, X.; Zuo, D.; Sun, L. Vitamin D3 analogue facilitates epithelial wound healing through promoting epithelial-mesenchymal transition via the Hippo pathway. J. Dermatol. Sci., 2020, 100(2), 120-128.
[http://dx.doi.org/10.1016/j.jdermsci.2020.08.015] [PMID: 32938565]
[24]
You, E.; Ko, P.; Jeong, J.; Keum, S.; Kim, J.W.; Seo, Y.J.; Song, W.K.; Rhee, S. Dynein-mediated nuclear translocation of yes-associated protein through microtubule acetylation controls fibroblast activation. Cell. Mol. Life Sci., 2020, 77(20), 4143-4161.
[http://dx.doi.org/10.1007/s00018-019-03412-x] [PMID: 31912196]
[25]
Yang, M.; Zhang, Y.; Fang, C.; Song, L.; Wang, Y.; Lu, L.; Yang, R.; Bu, Z.; Liang, X.; Zhang, K.; Fu, Q. Urine-microenvironment-initiated composite hydrogel patch reconfiguration propels scarless memory repair and reinvigoration of the urethra. Adv. Mater., 2022, 34(14), e2109522.
[http://dx.doi.org/10.1002/adma.202109522]
[26]
Zhuang, C.; Liu, Y.; Fu, S.; Yuan, C.; Luo, J.; Huang, X.; Yang, W.; Xie, W.; Zhuang, C. Silencing of lncRNA MIR497HG via CRISPR/Cas13d induces bladder cancer progression through promoting the crosstalk between hippo/yap and tgf-β/smad signaling. Front. Mol. Biosci., 2020, 7, 616768.
[http://dx.doi.org/10.3389/fmolb.2020.616768] [PMID: 33363213]
[27]
Brown, J.A.; Yonekubo, Y.; Hanson, N.; Sastre-Perona, A.; Basin, A.; Rytlewski, J.A.; Dolgalev, I.; Meehan, S.; Tsirigos, A.; Beronja, S.; Schober, M. TGF-β-induced quiescence mediates chemoresistance of tumor-propagating cells in squamous cell carcinoma. Cell Stem Cell, 2017, 21(5), 650-664.e8.
[http://dx.doi.org/10.1016/j.stem.2017.10.001] [PMID: 29100014]

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