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01-11-2021 | Esophageal Cancer | Original Article

Pyk2 level is a novel prognostic marker for patients with esophageal squamous cell carcinoma after radical surgery

Authors: Tong Zhu, Qiuxing Yang, Jingjing Shao, Zhuolin Chen, Bo Cai, Guoxin Mao

Published in: Virchows Archiv | Issue 5/2021

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors in East Asia. Surgical resection is currently the typical treatment. However, due to the highly invasive and metastatic characteristic of the disease, the mortality rate is still high. A search for potential prognostic biomarkers and therapeutic targets is very necessary. Here, we studied the expression of proline-rich tyrosine kinase 2 (Pyk2), a non-receptor tyrosine protein kinase, in ESCC and its influence on prognosis. A total of 112 cases of ESCC and paired adjacent normal tissues (NT) were organized in tissue microarray (TMA) from the Nantong First People’s Hospital. Our analysis of TMA revealed that Pyk2 levels were higher in ESCC than in paired adjacent NT by immunohistochemistry (p<0.001). Western blot and real-time quantitative PCR analysis (p=0.0359) also reached similar conclusions. To further explore the significance of Pyk2 in ESCC, another set of tissue microarrays was collected from the Affiliated Hospital of Nantong University, which includes 241 consecutive patients undergoing radical surgery for ESCC, to perform IHC scores. We demonstrated that the expression level of Pyk2 was positively correlated with N stage (node negative versus node positive, p=0.02) and clinical stage (I + II versus III + IV, p=0.042). Univariate and multivariate analyses suggested that high Pyk2 expression was an independent prognostic factor for overall survival with ESCC. Cell function studies found that Pyk2 promoted tumor proliferation and migration and reduced apoptosis. Pyk2 knockdown enhanced the sensitivity to cisplatin in ESCC cells. Western blot analysis confirmed that Pyk2 may promote tumor progression by activating the Akt signaling pathway.

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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492CrossRefPubMed

Zeng H, Chen W, Zheng R, Zhang S, Ji JS, Zou X, Xia C, Sun K, Yang Z, Li H, Wang N, Han R, Liu S, Li H, Mu H, He Y, Xu Y, Fu Z, Zhou Y, Jiang J, Yang Y, Chen J, Wei K, Fan D, Wang J, Fu F, Zhao D, Song G, Chen J, Jiang C, Zhou X, Gu X, Jin F, Li Q, Li Y, Wu T, Yan C, Dong J, Hua Z, Baade P, Bray F, Jemal A, Yu XQ, He J (2018) Changing cancer survival in China during 2003-15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Health 6:e555–555e567. https://doi.org/10.1016/S2214-109X(18)30127-XCrossRefPubMed

GBD (2017) Oesophageal Cancer Collaborators (2020) The global, regional, and national burden of oesophageal cancer and its attributable risk factors in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 5:582–597. https://doi.org/10.1016/S2468-1253(20)30007-8CrossRef

Arnold M, Soerjomataram I, Ferlay J, Forman D (2015) Global incidence of oesophageal cancer by histological subtype in 2012. Gut 64:381–387. https://doi.org/10.1136/gutjnl-2014-308124CrossRefPubMed

Yang Z, Zeng H, Xia R, Liu Q, Sun K, Zheng R, Zhang S, Xia C, Li H, Liu S, Zhang Z, Liu Y, Guo G, Song G, Zhu Y, Wu X, Song B, Liao X, Chen Y, Wei W, Zhuang G, Chen W (2018) Annual cost of illness of stomach and esophageal cancer patients in urban and rural areas in China: a multi-center study. Chin J Cancer Res 30:439–448. https://doi.org/10.21147/j.issn.1000-9604.2018.04.07CrossRefPubMedPubMedCentral

Takeuchi H, Miyata H, Gotoh M, Kitagawa Y, Baba H, Kimura W, Tomita N, Nakagoe T, Shimada M, Sugihara K, Mori M (2014) A risk model for esophagectomy using data of 5354 patients included in a Japanese nationwide web-based database. Ann Surg 260:259–266. https://doi.org/10.1097/SLA.0000000000000644CrossRefPubMed

Wang Z, Kang L, Zhang H, Huang Y, Fang L, Li M, Brown PJ, Arrowsmith CH, Li J, Wong J (2019) AKT drives SOX2 overexpression and cancer cell stemness in esophageal cancer by protecting SOX2 from UBR5-mediated degradation. Oncogene 38:5250–5264. https://doi.org/10.1038/s41388-019-0790-xCrossRefPubMed

Selitrennik M, Lev S (2015) PYK2 integrates growth factor and cytokine receptors signaling and potentiates breast cancer invasion via a positive feedback loop. Oncotarget 6:22214–22226. https://doi.org/10.18632/oncotarget.4257CrossRefPubMedPubMedCentral

Zhao T, Bao Y, Lu X, He Y, Gan X, Wang J, Liu B, Wang L (2018) Pyk2 promotes tumor progression in renal cell carcinoma. Oncol Lett 16:5953–5959. https://doi.org/10.3892/ol.2018.9412CrossRefPubMedPubMedCentral

10.

Hall JE, Fu W, Schaller MD (2011) Focal adhesion kinase: exploring Fak structure to gain insight into function. Int Rev Cell Mol Biol 288:185–225. https://doi.org/10.1016/B978-0-12-386041-5.00005-4CrossRefPubMed

11.

Kuang BH, Zhang MQ, Xu LH, Hu LJ, Wang HB, Zhao WF, Du Y, Zhang X (2013) Proline-rich tyrosine kinase 2 and its phosphorylated form pY881 are novel prognostic markers for non-small-cell lung cancer progression and patients’ overall survival. Br J Cancer 109:1252–1263. https://doi.org/10.1038/bjc.2013.439CrossRefPubMedPubMedCentral

12.

Zhang Y, Moschetta M, Huynh D, Tai YT, Zhang Y, Zhang W, Mishima Y, Ring JE, Tam WF, Xu Q, Maiso P, Reagan M, Sahin I, Sacco A, Manier S, Aljawai Y, Glavey S, Munshi NC, Anderson KC, Pachter J, Roccaro AM, Ghobrial IM (2014) Pyk2 promotes tumor progression in multiple myeloma. Blood 124:2675–2686. https://doi.org/10.1182/blood-2014-03-563981CrossRefPubMedPubMedCentral

13.

Hsiao YH, Huang YT, Hung CY, Kuo TC, Luo FJ, Yuan TC (2016) PYK2 via S6K1 regulates the function of androgen receptors and the growth of prostate cancer cells. Endocr Relat Cancer 23:651–663. https://doi.org/10.1530/ERC-16-0122CrossRefPubMed

14.

Al-Juboori SI, Vadakekolathu J, Idri S, Wagner S, Zafeiris D, Pearson JR, Almshayakhchi R, Caraglia M, Desiderio V, Miles AK, Boocock DJ, Ball GR, Regad T (2019) PYK2 promotes HER2-positive breast cancer invasion. J Exp Clin Cancer Res 38:210. https://doi.org/10.1186/s13046-019-1221-0CrossRefPubMedPubMedCentral

15.

Wang HY, Yao ZH, Tang H, Zhao Y, Jin SL, Zhou WP, Yao SN, Yang SJ, Liu YY, Luo SX (2017) A retrospective clinical study of comparing paclitaxel plus S-1 versus paclitaxel plus cisplatin as the first-line treatment for patients with advanced esophageal squamous cell carcinoma. Oncotarget 8:7540–7547. https://doi.org/10.18632/oncotarget.13602CrossRefPubMed

16.

Watanabe M, Otake R, Kozuki R, Toihata T, Takahashi K, Okamura A, Imamura Y (2020) Recent progress in multidisciplinary treatment for patients with esophageal cancer. Surg Today 50:12–20. https://doi.org/10.1007/s00595-019-01878-7CrossRefPubMed

17.

Zhu X, Bao Y, Guo Y, Yang W (2018) Proline-rich protein tyrosine kinase 2 in inflammation and cancer. Cancers (Basel) 10. https://doi.org/10.3390/cancers10050139

18.

Li HY, Cui XY, Wu W, Yu FY, Yao HR, Liu Q, Song EW, Chen JQ (2014) Pyk2 and Src mediate signaling to CCL18-induced breast cancer metastasis. J Cell Biochem 115:596–603. https://doi.org/10.1002/jcb.24697CrossRefPubMed

19.

Shen T, Guo Q (2018) Role of Pyk2 in human cancers. Med Sci Monit 24:8172–8182. https://doi.org/10.12659/MSM.913479CrossRefPubMedPubMedCentral

20.

Basile JR, Afkhami T, Gutkind JS (2005) Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway. Mol Cell Biol 25:6889–6898. https://doi.org/10.1128/MCB.25.16.6889-6898.2005CrossRefPubMedPubMedCentral

21.

Iiizumi M, Bandyopadhyay S, Pai SK, Watabe M, Hirota S, Hosobe S, Tsukada T, Miura K, Saito K, Furuta E, Liu W, Xing F, Okuda H, Kobayashi A, Watabe K (2008) RhoC promotes metastasis via activation of the Pyk2 pathway in prostate cancer. Cancer Res 68:7613–7620. https://doi.org/10.1158/0008-5472.CAN-07-6700CrossRefPubMedPubMedCentral

22.

Conte A, Kisslinger A, Procaccini C, Paladino S, Oliviero O, de Amicis F, Faicchia D, Fasano D, Caputo M, Matarese G, Pierantoni GM, Tramontano D (2016) Convergent effects of resveratrol and PYK2 on prostate cells. Int J Mol Sci 17. https://doi.org/10.3390/ijms17091542

23.

Li H, Gao Q, Guo L, Lu SH (2011) The PTEN/PI3K/Akt pathway regulates stem-like cells in primary esophageal carcinoma cells. Cancer Biol Ther 11:950–958. https://doi.org/10.4161/cbt.11.11.15531CrossRefPubMed

24.

Dong Y, Liang G, Yuan B, Yang C, Gao R, Zhou X (2015) MALAT1 promotes the proliferation and metastasis of osteosarcoma cells by activating the PI3K/Akt pathway. Tumour Biol 36:1477–1486. https://doi.org/10.1007/s13277-014-2631-4CrossRefPubMed

25.

Geng W, Ng KT, Sun CK, Yau WL, Liu XB, Cheng Q, Poon RT, Lo CM, Man K, Fan ST (2011) The role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in hepatocellular carcinoma. PLoS One 6:e27362. https://doi.org/10.1371/journal.pone.0027362CrossRefPubMedPubMedCentral

26.

Sohda M, Saito H, Kuriyama K, Yoshida T, Kumakura Y, Honjyo H, Hara K, Ozawa D, Suzuki S, Tanaka N, Sakai M, Miyazaki T, Fukuchi M, Kuwano H (2019) Post-esophagectomy adjuvant chemotherapy benefits esophageal cancer patients. Vivo 33:501–506. https://doi.org/10.21873/invivo.11502CrossRef

27.

Gao C, Chen G, Kuan SF, Zhang DH, Schlaepfer DD, Hu J (2015) FAK/PYK2 promotes the Wnt/β-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3β. Elife 4. https://doi.org/10.7554/eLife.10072

28.

Halder J, Lin YG, Merritt WM, Spannuth WA, Nick AM, Honda T, Kamat AA, Han LY, Kim TJ, Lu C, Tari AM, Bornmann W, Fernandez A, Lopez-Berestein G, Sood AK (2007) Therapeutic efficacy of a novel focal adhesion kinase inhibitor TAE226 in ovarian carcinoma. Cancer Res 67:10976–10983. https://doi.org/10.1158/0008-5472.CAN-07-2667CrossRefPubMed

29.

Shi Q, Hjelmeland AB, Keir ST, Song L, Wickman S, Jackson D, Ohmori O, Bigner DD, Friedman HS, Rich JN (2007) A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth. Mol Carcinog 46:488–496. https://doi.org/10.1002/mc.20297CrossRefPubMed

30.

Kanteti R, Mirzapoiazova T, Riehm JJ, Dhanasingh I, Mambetsariev B, Wang J, Kulkarni P, Kaushik G, Seshacharyulu P, Ponnusamy MP, Kindler HL, Nasser MW, Batra SK, Salgia R (2018) Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma. Cancer Biol Ther 19:316–327. https://doi.org/10.1080/15384047.2017.1416937CrossRefPubMedPubMedCentral

Title: Pyk2 level is a novel prognostic marker for patients with esophageal squamous cell carcinoma after radical surgery
Authors: Tong Zhu
Qiuxing Yang
Jingjing Shao
Zhuolin Chen
Bo Cai
Guoxin Mao
Publication date: 01-11-2021
Publisher: Springer Berlin Heidelberg
Keywords: Esophageal Cancer
Esophageal Cancer
Published in: Virchows Archiv / Issue 5/2021
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-021-03153-y

At a glance: The STEP trials

Springer Medicine

Pyk2 level is a novel prognostic marker for patients with esophageal squamous cell carcinoma after radical surgery

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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