PIN1 promotes the metastasis of cholangiocarcinoma cells by RACK1-mediated phosphorylation of ANXA2.

Publisher: Springer Country of Publication: Netherlands NLM ID: 101552938 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-3436 (Electronic) Linking ISSN: 22113428 NLM ISO Abbreviation: Cell Oncol (Dordr) Subsets: MEDLINE

Original Publication: Dordrecht : Springer

Cholangiocarcinoma*/pathology ; Cholangiocarcinoma*/metabolism ; Cholangiocarcinoma*/genetics ; Annexin A2*/metabolism ; Annexin A2*/genetics ; Bile Duct Neoplasms*/pathology ; Bile Duct Neoplasms*/metabolism ; Bile Duct Neoplasms*/genetics ; Receptors for Activated C Kinase*/metabolism ; Receptors for Activated C Kinase*/genetics ; NIMA-Interacting Peptidylprolyl Isomerase*/metabolism ; NIMA-Interacting Peptidylprolyl Isomerase*/genetics ; Cell Proliferation* ; Mice, Nude* ; Neoplasm Metastasis*; Humans ; Cell Line, Tumor ; Animals ; Phosphorylation ; Neoplasm Proteins/metabolism ; Neoplasm Proteins/genetics ; Mice ; Cell Movement/genetics ; Male ; Gene Expression Regulation, Neoplastic ; Cell Adhesion ; Female ; Mice, Inbred BALB C ; Prognosis ; Middle Aged

Background: Cholangiocarcinoma (CCA), a primary hepatobiliary malignancy, is characterized by a poor prognosis and a lack of effective treatments. Therefore, the need to explore novel therapeutic approaches is urgent. While the role of Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (PIN1) has been extensively studied in various tumor types, its involvement in CCA remains poorly understood.
Methods: In this study, we employed tissue microarray (TMA), reverse transcription-polymerase chain reaction (RT-PCR), and The Cancer Genome Atlas (TCGA) database to assess the expression of PIN1. Through in vitro and in vivo functional experiments, we investigated the impact of PIN1 on the adhesion and metastasis of CCA. Additionally, we explored downstream molecular pathways using RNA-seq, western blotting, co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques.
Results: Our findings revealed a negative correlation between PIN1 overexpression and prognosis in CCA tissues. Furthermore, high PIN1 expression promoted CCA cell proliferation and migration. Mechanistically, PIN1 functioned as an oncogene by regulating ANXA2 phosphorylation, thereby promoting CCA adhesion. Notably, the interaction between PIN1 and ANXA2 was facilitated by RACK1. Importantly, pharmacological inhibition of PIN1 using the FDA-approved drug all-trans retinoic acid (ATRA) effectively suppressed the metastatic potential of CCA cells in a nude mouse lung metastasis model.
Conclusion: Overall, our study emphasizes the critical role of the PIN1/RACK1/ANXA2 complex in CCA growth and functionality, highlighting the potential of targeting PIN1 as a promising therapeutic strategy for CCA.
(© 2024. Springer Nature Switzerland AG.)

B.J. Dwyer, E.J. Jarman, J. Gogoi-Tiwari, S. Ferreira-Gonzalez, L. Boulter, R.V. Guest, T.J. Kendall, D. Kurian, A.M. Kilpatrick, A.J. Robson, E. O’Duibhir, T.Y. Man, L. Campana, P.J. Starkey Lewis, S.J. Wigmore, J.K. Olynyk, G.A. Ramm, J.E.E. Tirnitz-Parker, S.J. Forbes, TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression. J. Hepatol. 74, 860–872 (2021). (PMID: 3322135210.1016/j.jhep.2020.11.018)
P. Lindnér, M. Rizell, L. Hafström, The impact of changed strategies for patients with cholangiocarcinoma in this millenium. HPB Surg. 2015, 736049 (2015). (PMID: 25788760434858410.1155/2015/736049)
S. Kamsa-Ard, V. Luvira, K. Suwanrungruang, S. Kamsa-Ard, V. Luvira, C. Santong, T. Srisuk, A. Pugkhem, V. Bhudhisawasdi, C. Pairojkul, Cholangiocarcinoma trends, incidence, and relative survival in Khon Kaen, Thailand from 1989 through 2013: a population-based cancer registry study. J. Epidemiol. 29, 197–204 (2019). (PMID: 30078813644579810.2188/jea.JE20180007)
E. Alabraba, H. Joshi, N. Bird, R. Griffin, R. Sturgess, N. Stern, C. Sieberhagen, T. Cross, A. Camenzuli, R. Davis, J. Evans, E. O’Grady, D. Palmer, R. Diaz-Nieto, S. Fenwick, G. Poston, H. Malik, Increased multimodality treatment options has improved survival for hepatocellular carcinoma but poor survival for biliary tract cancers remains unchanged. Eur. J. Surg. Oncol. 45, 1660–1667 (2019). (PMID: 3101498810.1016/j.ejso.2019.04.002)
B. Groot Koerkamp, J.K. Wiggers, P.J. Allen, M.G. Besselink, L.H. Blumgart, O.R. Busch, R.J. Coelen, M.I. D’Angelica, R.P. DeMatteo, D.J. Gouma, T.P. Kingham, W.R. Jarnagin, T.M. van Gulik, Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection. J. Am. College Surg. 221, 1041–1049 (2015). (PMID: 10.1016/j.jamcollsurg.2015.09.005)
W.A. Cambridge, C. Fairfield, J.J. Powell, E.M. Harrison, K. Søreide, S.J. Wigmore, R.V. Guest, Meta-analysis and meta-regression of survival after liver transplantation for unresectable perihilar cholangiocarcinoma. Ann. Surg. 273, 240–250 (2021). (PMID: 3209716410.1097/SLA.0000000000003801)
P.S. Steeg, Targeting metastasis. Nat. Rev. Cancer 16, 201–218 (2016). (PMID: 27009393705553010.1038/nrc.2016.25)
E.S. Yeh, A.R. Means, PIN1, the cell cycle and cancer. Nat. Rev. Cancer 7, 381–388 (2007). (PMID: 1741020210.1038/nrc2107)
A. Galat, Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity–targets–functions. Curr. Top. Med. Chem. 3, 1315–1347 (2003). (PMID: 1287116510.2174/1568026033451862)
K.P. Lu, X.Z. Zhou, The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease, Nature reviews. Mol. Cell Biol. 8, 904–916 (2007).
S. Wei, S. Kozono, L. Kats, M. Nechama, W. Li, J. Guarnerio, M. Luo, M.H. You, Y. Yao, A. Kondo, H. Hu, G. Bozkurt, N.J. Moerke, S. Cao, M. Reschke, C.H. Chen, E.M. Rego, F. Lo-Coco, L.C. Cantley, T.H. Lee, H. Wu, Y. Zhang, P.P. Pandolfi, X.Z. Zhou, K.P. Lu, Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat. Med. 21, 457–466 (2015). (PMID: 25849135442561610.1038/nm.3839)
K. Koikawa, S. Kibe, F. Suizu, N. Sekino, N. Kim, T.D. Manz, B.J. Pinch, D. Akshinthala, A. Verma, G. Gaglia, Y. Nezu, S. Ke, C. Qiu, K. Ohuchida, Y. Oda, T.H. Lee, B. Wegiel, J.G. Clohessy, N. London, S. Santagata, G.M. Wulf, M. Hidalgo, S.K. Muthuswamy, M. Nakamura, N.S. Gray, X.Z. Zhou, K.P. Lu, Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy. Cell 184, 4753–4771.e4727 (2021). (PMID: 34388391855735110.1016/j.cell.2021.07.020)
A. Lepore, P.M. Choy, N.C.W. Lee, M.A. Carella, R. Favicchio, M.A. Briones-Orta, S.S. Glaser, G. Alpini, C. D’Santos, R.M. Tooze, M. Lorger, W.K. Syn, A. Papakyriakou, G. Giamas, C. Bubici, S. Papa, Phosphorylation and stabilization of PIN1 by JNK promote intrahepatic cholangiocarcinoma growth. Hepatology 74, 2561–2579 (2021). (PMID: 3404806010.1002/hep.31983)
D.S. Chandrashekar, S.K. Karthikeyan, P.K. Korla, H. Patel, A.R. Shovon, M. Athar, G.J. Netto, Z.S. Qin, S. Kumar, U. Manne, C.J. Creighton, S. Varambally, UALCAN: an update to the integrated cancer data analysis platform. Neoplasia (New York, N.Y.) 25, 18–27 (2022). (PMID: 3507813410.1016/j.neo.2022.01.001)
D.S. Chandrashekar, B. Bashel, S.A.H. Balasubramanya, C.J. Creighton, I. Ponce-Rodriguez, B. Chakravarthi, S. Varambally, UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia (New York, N.Y.) 19, 649–658 (2017). (PMID: 2873221210.1016/j.neo.2017.05.002)
Y. Liu, H. Chen, X. Li, F. Zhang, L. Kong, X. Wang, J. Bai, X. Wu, PSMC2 regulates cell cycle progression through the p21/cyclin D1 pathway and predicts a poor prognosis in human hepatocellular carcinoma. Front. Oncol. 11, 607021 (2021). (PMID: 33718159795299510.3389/fonc.2021.607021)
X. Wu, H. Chen, Q. Gao, J. Bai, X. Wang, J. Zhou, S. Qiu, Y. Xu, Y. Shi, X. Wang, J. Zhou, J. Fan, Downregulation of JWA promotes tumor invasion and predicts poor prognosis in human hepatocellular carcinoma. Mol. Carcinog. 53, 325–336 (2014). (PMID: 2316906210.1002/mc.21981)
T. Zhou, Y. Zhang, Y. Chen, J. Shan, J. Wang, Y. Wang, J. Chang, W. Jiang, R. Chen, Z. Wang, X. Shi, Y. Yu, C. Li, X. Li, ROBO1 p.E280* loses the inhibitory effects on the proliferation and angiogenesis of wild-type ROBO1 in cholangiocarcinoma by interrupting SLIT2 signal. Front. Oncol. 12, 879963 (2022). (PMID: 35615148912497410.3389/fonc.2022.879963)
J.B. Andersen, B. Spee, B.R. Blechacz, I. Avital, M. Komuta, A. Barbour, E.A. Conner, M.C. Gillen, T. Roskams, L.R. Roberts, V.M. Factor, S.S. Thorgeirsson, Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 142, 1021–1031.e1015 (2012). (PMID: 2217858910.1053/j.gastro.2011.12.005)
K.S. Ahn, D. O’Brien, Y.N. Kang, T. Mounajjed, Y.H. Kim, T.S. Kim, J.A. Kocher, L.K. Allotey, M.J. Borad, L.R. Roberts, K.J. Kang, Prognostic subclass of intrahepatic cholangiocarcinoma by integrative molecular-clinical analysis and potential targeted approach. Hepatol. Int. 13, 490–500 (2019). (PMID: 3121487510.1007/s12072-019-09954-3)
H. Hamidi, J. Ivaska, Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer 18, 533–548 (2018). (PMID: 30002479662954810.1038/s41568-018-0038-z)
Y. Jung, J. Wang, J. Song, Y. Shiozawa, J. Wang, A. Havens, Z. Wang, Y.X. Sun, S.G. Emerson, P.H. Krebsbach, R.S. Taichman, Annexin II expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. Blood 110, 82–90 (2007). (PMID: 17360942189613010.1182/blood-2006-05-021352)
C. Zhang, T. Zhou, Z. Chen, M. Yan, B. Li, H. Lv, C. Wang, S. Xiang, L. Shi, Y. Zhu, D. Ai, Coupling of integrin α5 to annexin A2 by flow drives endothelial activation. Circ. Res. 127, 1074–1090 (2020). (PMID: 3267351510.1161/CIRCRESAHA.120.316857)
Z. Su, T.R. Shelite, Y. Qiu, Q. Chang, M. Wakamiya, J. Bei, X. He, C. Zhou, Y. Liu, E. Nyong, Y. Liang, A. Gaitas, T.B. Saito, B. Gong, Host EPAC1 modulates rickettsial adhesion to vascular endothelial cells via regulation of ANXA2 Y23 phosphorylation. Pathogens (Basel, Switzerland) 10, 1307 (2021). (PMID: 34684255)
S.Z. Shalhout, P.Y. Yang, E.M. Grzelak, K. Nutsch, S. Shao, C. Zambaldo, J. Iaconelli, L. Ibrahim, C. Stanton, S.R. Chadwick, E. Chen, M. DeRan, S. Li, M. Hull, X. Wu, A.K. Chatterjee, W. Shen, F.D. Camargo, P.G. Schultz, M.J. Bollong, YAP-dependent proliferation by a small molecule targeting annexin A2. Nat. Chem. Biol. 17, 767–775 (2021). (PMID: 3372343110.1038/s41589-021-00755-0)
A.S. Farrell, C. Pelz, X. Wang, C.J. Daniel, Z. Wang, Y. Su, M. Janghorban, X. Zhang, C. Morgan, S. Impey, R.C. Sears, Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis. Mol. Cell. Biol. 33, 2930–2949 (2013). (PMID: 23716601371967410.1128/MCB.01455-12)
X.H. Liao, A.L. Zhang, M. Zheng, M.Q. Li, C.P. Chen, H. Xu, Q.S. Chu, D. Yang, W. Lu, T.F. Tsai, H. Liu, X.Z. Zhou, K.P. Lu, Chemical or genetic Pin1 inhibition exerts potent anticancer activity against hepatocellular carcinoma by blocking multiple cancer-driving pathways. Sci. Rep. 7, 43639 (2017). (PMID: 28262728533794710.1038/srep43639)
N. Razumilava, G.J. Gores, Cholangiocarcinoma. Lancet (London, England) 383, 2168–2179 (2014). (PMID: 2458168210.1016/S0140-6736(13)61903-0)
P.J. Brindley, M. Bachini, S.I. Ilyas, S.A. Khan, A. Loukas, A.E. Sirica, B.T. Teh, S. Wongkham, G.J. Gores, Cholangiocarcinoma. Nat. Rev. Dis. Primers 7, 65 (2021). (PMID: 34504109924647910.1038/s41572-021-00300-2)
X. Lian, Y.M. Lin, S. Kozono, M.K. Herbert, X. Li, X. Yuan, J. Guo, Y. Guo, M. Tang, J. Lin, Y. Huang, B. Wang, C. Qiu, C.Y. Tsai, J. Xie, Z.J. Gao, Y. Wu, H. Liu, X.Z. Zhou, K.P. Lu, Y. Chen, Pin1 inhibition exerts potent activity against acute myeloid leukemia through blocking multiple cancer-driving pathways. J. Hematol. Oncol. 11, 73 (2018). (PMID: 29848341597746010.1186/s13045-018-0611-7)
C. Liang, S. Shi, M. Liu, Y. Qin, Q. Meng, J. Hua, S. Ji, Y. Zhang, J. Yang, J. Xu, Q. Ni, M. Li, X. Yu, PIN1 maintains redox balance via the c-Myc/NRF2 axis to counteract kras-induced mitochondrial respiratory injury in pancreatic cancer cells. Cancer Res. 79, 133–145 (2019). (PMID: 3035562010.1158/0008-5472.CAN-18-1968)
J.E. Girardini, M. Napoli, S. Piazza, A. Rustighi, C. Marotta, E. Radaelli, V. Capaci, L. Jordan, P. Quinlan, A. Thompson, M. Mano, A. Rosato, T. Crook, E. Scanziani, A.R. Means, G. Lozano, C. Schneider, G. Del Sal, A Pin1/mutant p53 axis promotes aggressiveness in breast cancer. Cancer Cell. 20, 79–91 (2011). (PMID: 2174159810.1016/j.ccr.2011.06.004)
U. Jamiyandorj, J.S. Bae, S.J. Noh, S. Jachin, J.E. Choi, K.Y. Jang, M.J. Chung, M.J. Kang, D.G. Lee, W.S. Moon, Expression of peptidyl-prolyl isomerase PIN1 and its role in the pathogenesis of extrahepatic cholangiocarcinoma. Oncol. Lett. 6, 1421–1426 (2013). (PMID: 24179535381380210.3892/ol.2013.1525)
L. Ng, V. Kwan, A. Chow, T.C. Yau, R.T. Poon, R. Pang, W.L. Law, Overexpression of Pin1 and rho signaling partners correlates with metastatic behavior and poor recurrence-free survival of hepatocellular carcinoma patients. BMC Cancer 19, 713 (2019). (PMID: 31324164664248210.1186/s12885-019-5919-3)
J.S. Pyo, B.K. Son, I.H. Oh, Cytoplasmic Pin1 expression is correlated with poor prognosis in colorectal cancer. Pathol. Res. Pract. 214, 1848–1853 (2018). (PMID: 3024494610.1016/j.prp.2018.09.018)
Q. Sun, G. Fan, Q. Zhuo, W. Dai, Z. Ye, S. Ji, W. Xu, W. Liu, Q. Hu, Z. Zhang, M. Liu, X. Yu, X. Xu, Y. Qin, Pin1 promotes pancreatic cancer progression and metastasis by activation of NF-κB-IL-18 feedback loop. Cell Prolif. 53, e12816 (2020). (PMID: 32347623726007510.1111/cpr.12816)
J.A. Spijkers-Hagelstein, S. Mimoso Pinhanços, P. Schneider, R. Pieters, R.W. Stam, Src kinase-induced phosphorylation of annexin A2 mediates glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia. Leukemia 27, 1063–1071 (2013). (PMID: 2333436210.1038/leu.2012.372)
J.S. Menell, G.M. Cesarman, A.T. Jacovina, M.A. McLaughlin, E.A. Lev, K.A. Hajjar, Annexin II and bleeding in acute promyelocytic leukemia. N. Engl. J. Med. 340, 994–1004 (1999). (PMID: 1009914110.1056/NEJM199904013401303)
M.R. Sharma, L. Koltowski, R.T. Ownbey, G.P. Tuszynski, M.C. Sharma, Angiogenesis-associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression. Exp. Mol. Pathol. 81, 146–156 (2006). (PMID: 1664389210.1016/j.yexmp.2006.03.003)
K. Emoto, Y. Yamada, H. Sawada, H. Fujimoto, M. Ueno, T. Takayama, K. Kamada, A. Naito, S. Hirao, Y. Nakajima, Annexin II overexpression correlates with stromal tenascin-C overexpression: a prognostic marker in colorectal carcinoma. Cancer 92, 1419–1426 (2001). (PMID: 1174521810.1002/1097-0142(20010915)92:6<1419::AID-CNCR1465>3.0.CO;2-J)
B.J. Roseman, A. Bollen, J. Hsu, K. Lamborn, M.A. Israel, Annexin II marks astrocytic brain tumors of high histologic grade. Oncol. Res. 6, 561–567 (1994). (PMID: 7787249)
J. Wang, L. Deng, H. Zhuang, J. Liu, D. Liu, X. Li, S. Jin, L. Zhu, H. Wang, B. Lin, Interaction of HE4 and ANXA2 exists in various malignant cells-HE4-ANXA2-MMP2 protein complex promotes cell migration. Cancer Cell Int. 19, 161 (2019). (PMID: 31210752656740610.1186/s12935-019-0864-4)
T. Garrido-Gómez, N. Castillo-Marco, T. Cordero, C. Simón, Decidualization resistance in the origin of preeclampsia. Am. J. Obstet. Gynecol. 226, S886–s894 (2022). (PMID: 3300727010.1016/j.ajog.2020.09.039)
S. Ma, C.C. Lu, L.Y. Yang, J.J. Wang, B.S. Wang, H.Q. Cai, J.J. Hao, X. Xu, Y. Cai, Y. Zhang, M.R. Wang, ANXA2 promotes esophageal cancer progression by activating MYC-HIF1A-VEGF axis. J. Exp. Clin. Cancer Res. 37, 183 (2018). (PMID: 30081903609118010.1186/s13046-018-0851-y)
D.R. Adams, D. Ron, P.A. Kiely, RACK1, a multifaceted scaffolding protein: structure and function. Cell Commun. Signal. 9, 22 (2011). (PMID: 21978545319572910.1186/1478-811X-9-22)
F. Hu, Z. Tao, M. Wang, G. Li, Y. Zhang, H. Zhong, H. Xiao, X. Xie, M. Ju, RACK1 promoted the growth and migration of the cancer cells in the progression of esophageal squamous cell carcinoma. Tumour. Biol. 34, 3893–3899 (2013). (PMID: 2389338410.1007/s13277-013-0977-7)
Y. Fan, W. Si, W. Ji, Z. Wang, Z. Gao, R. Tian, W. Song, H. Zhang, R. Niu, F. Zhang, Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells. Breast Cancer Res. 21, 66 (2019). (PMID: 31113450653002410.1186/s13058-019-1147-7)
Y. Yang, N. Wu, Z. Wang, F. Zhang, R. Tian, W. Ji, X. Ren, R. Niu, Rack1 mediates the interaction of P-glycoprotein with Anxa2 and regulates migration and invasion of multidrug-resistant breast cancer cells. Int. J. Mol. Sci. 17, 1718 (2016). (PMID: 27754360508574910.3390/ijms17101718)
Q.L. Lv, Y.T. Huang, G.H. Wang, Y.L. Liu, J. Huang, Q. Qu, B. Sun, L. Hu, L. Cheng, S.H. Chen, H.H. Zhou, Overexpression of RACK1 promotes metastasis by enhancing epithelial-mesenchymal transition and predicts poor prognosis in human glioma. Int. J. Environ. Res. Public Health 13, 1021 (2016). (PMID: 27763568508676010.3390/ijerph13101021)
W. Wu, X. Xue, Y. Chen, N. Zheng, J. Wang, Targeting prolyl isomerase Pin1 as a promising strategy to overcome resistance to cancer therapies. Pharmacol. Res. 184, 106456 (2022). (PMID: 3611670910.1016/j.phrs.2022.106456)

82102150 National Natural Science Foundation of China; 81472306 National Natural Science Foundation of China; BK20210968 Natural Science Foundation of Jiangsu Province; YNRCZN015 Special Fund for Talents of the Jiangsu Province Hospital

Keywords: ATRA; Adhesion; Cholangiocarcinoma; Metastasis; PIN1

0 (Annexin A2)
0 (Receptors for Activated C Kinase)
0 (NIMA-Interacting Peptidylprolyl Isomerase)
0 (ANXA2 protein, human)
0 (RACK1 protein, human)
EC 5.2.1.8 (PIN1 protein, human)
0 (Neoplasm Proteins)

Date Created: 20240222 Date Completed: 20240813 Latest Revision: 20240924

20240924

10.1007/s13402-024-00924-y

38386231