眾所周知，CASZ1 是一種具有兩種亞型的鋅指轉錄因子，在心臟和大腦發育中起著至關重要的作用。 儘管 CASZ1 通常在一系列癌症中異常表達，但其後果因腫瘤種類而異。 例如，雖然它促進了卵巢癌的癌症擴散，但它在神經母細胞瘤中起到了腫瘤抑制因子的作用。 CASZ1 對最致命的惡性腫瘤肺癌的影響尚不清楚。 在這裡，我們發現肺癌 CASZ1 表達與不良預後和癌症轉移之間存在很強的相關性。 抑制肺癌細胞的上皮-間質轉化、遷移和侵襲以及體內轉移的減少都是CASZ1敲低的作用。 在 CASZ1 沉默的細胞中，RNA 測序研究表明 CASZ1 對整合素介導的通路有重大影響。 ITGAV 轉錄受 CASZ1 與 ITGAV 啟動子結合的調控。 我們的研究表明，CASZ1 在肺癌中具有致癌功能，並且 ITGAV 介導 CASZ1 以促進肺癌的侵襲、遷移和轉移。

It is widely known that CASZ1, a zinc finger transcription factor with two isoforms, plays crucial functions in cardiac and brain development. Although CASZ1 is typically expressed abnormally in a range of cancers, the consequences vary depending on the kind of tumor. For instance, while it promotes cancer spread in ovarian cancer, it works as a tumor suppressor in neuroblastoma. The impact of CASZ1 on lung cancer, the most deadly malignancy, is yet unknown. Here, we found a strong correlation between lung cancer CASZ1 expression and poor prognosis and cancer metastasis. The inhibition of the epithelial-mesenchymal transition, migration, and invasion of lung cancer cells as well as the reduction of in vivo metastasis were all effects of CASZ1 knockdown. In CASZ1-silenced cells, RNA sequencing research revealed that CASZ1 has a major impact on integrin-mediated pathways. ITGAV transcription is regulated by CASZ1 binding to the ITGAV promoter. Our research shows that CASZ1 has an oncogenic function in lung cancer and that ITGAV mediates CASZ1 to facilitate lung cancer invasion, migration, and metastasis.

[1] Thandra KC, Barsouk A, Saginala K, Aluru JS and Barsouk A. Epidemiology of lung cancer. Contemp Oncol (Pozn) 2021; 25: 45-52.
[2] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71: 209-249.
[3] Riihimaki M, Hemminki A, Fallah M, Thomsen H, Sundquist K, Sundquist J and Hemminki K. Metastatic sites and survival in lung cancer. Lung Cancer 2014; 86: 78-84.
[4] Zhang Y and Weinberg RA. Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Front Med 2018; 12: 361-373.
[5] Ell B and Kang Y. Transcriptional control of cancer metastasis. Trends Cell Biol 2013; 23: 603-611.
[6] Mellerick DM, Kassis JA, Zhang SD and Odenwald WF. castor encodes a novel zinc finger protein required for the development of a subset of CNS neurons in Drosophila. Neuron 1992; 9: 789-803.
[7] Liu Z, Yang X, Tan F, Cullion K and Thiele CJ. Molecular cloning and characterization of human Castor, a novel human gene upregulated during cell differentiation. Biochem Biophys Res Commun 2006; 344: 834-844.
[8] Virden RA, Thiele CJ and Liu Z. Characterization of critical domains within the tumor suppressor CASZ1 required for transcriptional regulation and growth suppression. Mol Cell Biol 2012; 32: 1518-1528.
[9] Charpentier MS, Christine KS, Amin NM, Dorr KM, Kushner EJ, Bautch VL, Taylor JM and Conlon FL. CASZ1 promotes vascular assembly and morphogenesis through the direct regulation of an EGFL7/RhoA-mediated pathway. Dev Cell 2013; 25: 132-143.
[10] Liu Z, Li W, Ma X, Ding N, Spallotta F, Southon E, Tessarollo L, Gaetano C, Mukouyama YS and Thiele CJ. Essential role of the zinc finger transcription factor Casz1 for mammalian cardiac morphogenesis and development. J Biol Chem 2014; 289: 29801-29816.
[11] Bhaskaran N, Liu Z, Saravanamuthu SS, Yan C, Hu Y, Dong L, Zelenka P, Zheng L, Bletsos V, Harris R, Harrington B, Weinberg A, Thiele CJ, Ye F and Pandiyan P. Identification of Casz1 as a Regulatory Protein Controlling T Helper Cell Differentiation, Inflammation, and Immunity. Front Immunol 2018; 9: 184.
[12] Liu Z, Yang X, Li Z, McMahon C, Sizer C, Barenboim-Stapleton L, Bliskovsky V, Mock B, Ried T, London WB, Maris J, Khan J and Thiele CJ. CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression. Cell Death Differ 2011; 18: 1174-1183.
[13] Wang JL, Yang MY, Xiao S, Sun B, Li YM and Yang LY. Downregulation of castor zinc finger 1 predicts poor prognosis and facilitates hepatocellular carcinoma progression via MAPK/ERK signaling. J Exp Clin Cancer Res 2018; 37: 45.
[14] Wu YY, Chang CL, Chuang YJ, Wu JE, Tung CH, Chen YC, Chen YL, Hong TM and Hsu KF. CASZ1 is a novel promoter of metastasis in ovarian cancer. Am J Cancer Res 2016; 6: 1253-1270.
[15] Hamidi H and Ivaska J. Every step of the way: integrins in cancer progression and metastasis. Nat Rev Cancer 2018; 18: 533-548.
[16] Desgrosellier JS and Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010; 10: 9-22.
[17] Waisberg J, De Souza Viana L, Affonso Junior RJ, Silva SR, Denadai MV, Margeotto FB, De Souza CS and Matos D. Overexpression of the ITGAV gene is associated with progression and spread of colorectal cancer. Anticancer Res 2014; 34: 5599-5607.
[18] Wang H, Chen H, Jiang Z, Lin Y, Wang X, Xiang J and Peng J. Integrin subunit alpha V promotes growth, migration, and invasion of gastric cancer cells. Pathol Res Pract 2019; 215: 152531.
[19] Retta SF, Cassara G, D'Amato M, Alessandro R, Pellegrino M, Degani S, De Leo G, Silengo L and Tarone G. Cross talk between beta(1) and alpha(V) integrins: beta(1) affects beta(3) mRNA stability. Mol Biol Cell 2001; 12: 3126-3138.
[20] Cheuk IW, Siu MT, Ho JC, Chen J, Shin VY and Kwong A. ITGAV targeting as a therapeutic approach for treatment of metastatic breast cancer. Am J Cancer Res 2020; 10: 211-223.
[21] Slack RJ, Macdonald SJF, Roper JA, Jenkins RG and Hatley RJD. Emerging therapeutic opportunities for integrin inhibitors. Nat Rev Drug Discov 2022; 21: 60-78.
[22] Chu YW, Yang PC, Yang SC, Shyu YC, Hendrix MJ, Wu R and Wu CW. Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol 1997; 17: 353-360.
[23] Wang X, Shi D, Zhao D and Hu D. Aberrant Methylation and Differential Expression of SLC2A1, TNS4, GAPDH, ATP8A2, and CASZ1 Are Associated with the Prognosis of Lung Adenocarcinoma. Biomed Res Int 2020; 2020: 1807089.
[24] Mittal V. Epithelial Mesenchymal Transition in Aggressive Lung Cancers. Adv Exp Med Biol 2016; 890: 37-56.
[25] Kalluri R and Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119: 1420-1428.
[26] Lim J and Thiery JP. Epithelial-mesenchymal transitions: insights from development. Development 2012; 139: 3471-3486.
[27] Zeisberg M and Kalluri R. Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am J Physiol Cell Physiol 2013; 304: C216-225.
[28] Thiery JP, Acloque H, Huang RY and Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139: 871-890.
[29] Nieto MA. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 2011; 27: 347-376.
[30] Tam WL and Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 2013; 19: 1438-1449.
[31] Chaffer CL, Thompson EW and Williams ED. Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs 2007; 185: 7-19.
[32] Chaw SY, Abdul Majeed A, Dalley AJ, Chan A, Stein S and Farah CS. Epithelial to mesenchymal transition (EMT) biomarkers--E-cadherin, beta-catenin, APC and Vimentin--in oral squamous cell carcinogenesis and transformation. Oral Oncol 2012; 48: 997-1006.
[33] Smith BN and Bhowmick NA. Role of EMT in Metastasis and Therapy Resistance. J Clin Med 2016; 5:
[34] Thomas GJ, Lewis MP, Hart IR, Marshall JF and Speight PM. AlphaVbeta6 integrin promotes invasion of squamous carcinoma cells through up-regulation of matrix metalloproteinase-9. Int J Cancer 2001; 92: 641-650.
[35] Lu JG, Li Y, Li L and Kan X. Overexpression of osteopontin and integrin alphav in laryngeal and hypopharyngeal carcinomas associated with differentiation and metastasis. J Cancer Res Clin Oncol 2011; 137: 1613-1618.
[36] Massuto DA, Kneese EC, Johnson GA, Burghardt RC, Hooper RN, Ing NH and Jaeger LA. Transforming growth factor beta (TGFB) signaling is activated during porcine implantation: proposed role for latency-associated peptide interactions with integrins at the conceptus-maternal interface. Reproduction 2010; 139: 465-478.