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SLC34A2 simultaneously promotes papillary thyroid carcinoma growth and invasion through distinct mechanisms

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Abstract

Thyroid cancer is the fastest growing cancer among all solid tumors in recent decades. Papillary thyroid carcinoma (PTC) is the most predominant type of thyroid cancer. Around 30% of PTC patients with distant metastases and local invasion receive poor prognosis. Thus, the identification of new druggable biological targets is of great importance. Accumulating evidence indicates that solute carrier family numbers have emerged as obligate effectors during the progression of multiple malignancies. Here, we uncovered the functional significance, molecular mechanisms, and clinical impact of solute carrier family 34 member A2 (SLC34A2) in PTC. SLC34A2 was markedly overexpressed in PTC tissues at both mRNA and protein levels compared with matched adjacent normal tissues due to promoter hypomethylation mediated by the DNA methyltransferase 3 beta (DNMT3B). Furthermore, a series of in vivo and in vitro gain- or loss-of-functional assays elucidated the role of SLC34A2 in boosting cell proliferation, cell cycle progression, migration, invasion, and adhesion of PTC cells. Using immunoprecipitation and mass spectrometry, we discovered that SLC34A2 bound to the actin-binding repeats domain of Cortactin (CTTN), thereby inducing the invadopodia formation of PTC cells to promote the metastasis potential of PTC cells. Besides, our mechanistic studies, as well as gene set enrichment analysis (GSEA), have pinpointed the PTEN/AKT/FOXO3a pathway as a major signaling functioning downstream of SLC34A2 regulated cell growth. Taken together, our results highlighted that SLC34A2 plays a pivotal oncogenic role during carcinogenesis and metastasis through distinct mechanisms in PTC.

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Fig. 1: Upregulation of SLC34A2 is related to lymph node metastasis in PTC samples.
Fig. 2: Overexpression of SLC34A2 is inversely correlated with promoter DNA hypomethylation in PTC cells and tissues.
Fig. 3: SLC34A2 facilitates PTC proliferation through accelerating G1/S phase transition.
Fig. 4: SLC34A2 interacts with CTTN and activates RhoA/ROCK-1 signaling pathway.
Fig. 5: SLC34A2 promotes the migratory and invasive potential of PTC cells through inducing invadopodia formation.
Fig. 6: SLC34A2 regulates cell cycle checkpoint kinases expression through the AKT/FOXO3a pathway.
Fig. 7: Inhibition of SLC34A2 combined with MK2206 suppresses tumor growth in vivo.
Fig. 8: CTTN is required for SLC34A2-induced metastasis of PTC cells in vivo.

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    Article  Google Scholar 

  3. Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet. 2016;388:2783–95.

    Article  CAS  Google Scholar 

  4. Lacerda-Abreu MA, Russo-Abrahao T, Monteiro RQ, Rumjanek FD, Meyer-Fernandes JR. Inorganic phosphate transporters in cancer: functions, molecular mechanisms and possible clinical applications. Biochim Biophys Acta Rev Cancer. 2018;1870:291–8.

    Article  CAS  Google Scholar 

  5. Hernando N, Wagner CA. Mechanisms and regulation of intestinal phosphate absorption. Compr Physiol. 2018;8:1065–90.

    Article  Google Scholar 

  6. Kareva I. Biological stoichiometry in tumor micro-environments. PLoS ONE. 2013;8:e51844.

    Article  CAS  Google Scholar 

  7. Wagner CA, Hernando N, Forster IC, Biber J. The SLC34 family of sodium-dependent phosphate transporters. Pflug Arch. 2014;466:139–53.

    Article  CAS  Google Scholar 

  8. Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL, Berge EM, et al. Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clin Cancer Res. 2012;18:4570–9.

    Article  CAS  Google Scholar 

  9. Neel DS, Allegakoen DV, Olivas V, Mayekar MK, Hemmati G, Chatterjee N, et al. Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins. Cancer Res. 2019;79:546–56.

    Article  CAS  Google Scholar 

  10. Chen DR, Chien SY, Kuo SJ, Teng YH, Tsai HT, Kuo JH, et al. SLC34A2 as a novel marker for diagnosis and targeted therapy of breast cancer. Anticancer Res. 2010;30:4135–40.

    PubMed  Google Scholar 

  11. Rangel LB, Sherman-Baust CA, Wernyj RP, Schwartz DR, Cho KR, Morin PJ. Characterization of novel human ovarian cancer-specific transcripts (HOSTs) identified by serial analysis of gene expression. Oncogene. 2003;22:7225–32.

    Article  CAS  Google Scholar 

  12. Liu X, Zhou X, Xu H, He Z, Shi X, Wu S. SLC34A2 regulates the proliferation, migration, and invasion of human osteosarcoma cells through PTEN/PI3K/AKT signaling. DNA Cell Biol. 2017;36:775–80.

    Article  CAS  Google Scholar 

  13. Fisher KE, Yin-Goen Q, Alexis D, Sirintrapun JS, Harrison W, Benjamin IR, et al. Gene expression profiling of clear cell papillary renal cell carcinoma: comparison with clear cell renal cell carcinoma and papillary renal cell carcinoma. Mod Pathol. 2014;27:222–30.

    Article  CAS  Google Scholar 

  14. Wang Y, Yang W, Pu Q, Yang Y, Ye S, Ma Q, et al. The effects and mechanisms of SLC34A2 in tumorigenesis and progression of human non-small cell lung cancer. J Biomed Sci. 2015;22:52.

    Article  Google Scholar 

  15. Jarzab B, Wiench M, Fujarewicz K, Simek K, Jarzab M, Oczko-Wojciechowska M, et al. Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications. Cancer Res. 2005;65:1587–97.

    Article  CAS  Google Scholar 

  16. Li Y, Yang Q, Guan H, Shi B, Ji M, Hou P. ZNF677 suppresses Akt phosphorylation and tumorigenesis in thyroid cancer. Cancer Res. 2018;78:5216–28.

    Article  CAS  Google Scholar 

  17. Cesar-Razquin A, Snijder B, Frappier-Brinton T, Isserlin R, Gyimesi G, Bai X, et al. A call for systematic research on solute carriers. Cell. 2015;162:478–87.

    Article  CAS  Google Scholar 

  18. Wong CC, Qian Y, Li X, Xu J, Kang W, Tong JH, et al. SLC25A22 promotes proliferation and survival of colorectal cancer cells with KRAS mutations and xenograft tumor progression in mice via intracellular synthesis of aspartate. Gastroenterology. 2016;151:945–60.

    Article  CAS  Google Scholar 

  19. Gamble LD, Purgato S, Murray J, **ao L, Yu D, Hanssen KM, et al. Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma. Sci Transl Med. 2019;11:eaau1099.

  20. He J, ** Y, Zhou M, Li X, Chen W, Wang Y, et al. Solute carrier family 35 member F2 is indispensable for papillary thyroid carcinoma progression through activation of transforming growth factor-beta type I receptor/apoptosis signal-regulating kinase 1/mitogen-activated protein kinase signaling axis. Cancer Sci. 2018;109:642–55.

    Article  CAS  Google Scholar 

  21. ** H, Xu CX, Lim HT, Park SJ, Shin JY, Chung YS, et al. High dietary inorganic phosphate increases lung tumorigenesis and alters Akt signaling. Am J Respir Crit Care Med. 2009;179:59–68.

    Article  CAS  Google Scholar 

  22. Spina A, Sorvillo L, Di Maiolo F, Esposito A, D’Auria R, Di Gesto D, et al. Inorganic phosphate enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin via a p53-dependent pathway. J Cell Physiol. 2013;228:198–206.

    Article  CAS  Google Scholar 

  23. Wong CC, Qian Y, Yu J. Interplay between epigenetics and metabolism in oncogenesis: mechanisms and therapeutic approaches. Oncogene. 2017;36:3359–74.

    Article  CAS  Google Scholar 

  24. Weisenberger DJ, Liang G, Lenz HJ. DNA methylation aberrancies delineate clinically distinct subsets of colorectal cancer and provide novel targets for epigenetic therapies. Oncogene. 2018;37:566–77.

    Article  CAS  Google Scholar 

  25. Ricketts CJ, Morris MR, Gentle D, Brown M, Wake N, Woodward ER, et al. Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma. Epigenetics. 2012;7:278–90.

    Article  CAS  Google Scholar 

  26. Yousefi M, Nosrati R, Salmaninejad A, Dehghani S, Shahryari A, Saberi A. Organ-specific metastasis of breast cancer: molecular and cellular mechanisms underlying lung metastasis. Cell Oncol. 2018;41:123–40.

    Article  CAS  Google Scholar 

  27. Eddy RJ, Weidmann MD, Sharma VP, Condeelis JS. Tumor cell invadopodia: invasive protrusions that orchestrate metastasis. Trends Cell Biol. 2017;27:595–607.

    Article  CAS  Google Scholar 

  28. Jeannot P, Besson A. Cortactin function in invadopodia. Small GTPases. 2017. p. 1–15. https://doi.org/10.1080/21541248.2017.1405773.

  29. Mader CC, Oser M, Magalhaes MA, Bravo-Cordero JJ, Condeelis J, Koleske AJ, et al. An EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Cancer Res. 2011;71:1730–41.

    Article  CAS  Google Scholar 

  30. Watkins RJ, Imruetaicharoenchoke W, Read ML, Sharma N, Poole VL, Gentilin E, et al. Pro-invasive effect of proto-oncogene PBF is modulated by an interaction with Cortactin. J Clin Endocrinol Metab. 2016;101:4551–63.

    Article  CAS  Google Scholar 

  31. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  Google Scholar 

  32. Ramirez-Moya J, Wert-Lamas L, Santisteban P. MicroRNA-146b promotes PI3K/AKT pathway hyperactivation and thyroid cancer progression by targeting PTEN. Oncogene. 2018;37:3369–83.

    Article  CAS  Google Scholar 

  33. Kim S, Lee E, Jung J, Lee JW, Kim HJ, Kim J, et al. microRNA-155 positively regulates glucose metabolism via PIK3R1-FOXO3a-cMYC axis in breast cancer. Oncogene. 2018;37:2982–91.

    Article  CAS  Google Scholar 

  34. Lv S, Ji L, Chen B, Liu S, Lei C, Liu X, et al. Histone methyltransferase KMT2D sustains prostate carcinogenesis and metastasis via epigenetically activating LIFR and KLF4. Oncogene. 2018;37:1354–68.

    Article  CAS  Google Scholar 

  35. Crowell JA, Steele VE, Fay JR. Targeting the AKT protein kinase for cancer chemoprevention. Mol Cancer Ther. 2007;6:2139–48.

    Article  CAS  Google Scholar 

  36. Calnan DR, Brunet A. The FoxO code. Oncogene. 2008;27:2276–88.

    Article  CAS  Google Scholar 

  37. Li Y, Chen X, Lu H. Knockdown of SLC34A2 inhibits hepatocellular carcinoma cell proliferation and invasion. Oncol Res. 2016;24:511–9.

    Article  Google Scholar 

  38. Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther. 2010;9:1956–67.

    Article  CAS  Google Scholar 

  39. Lin K, Rubinfeld B, Zhang C, Firestein R, Harstad E, Roth L, et al. Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. Clin Cancer Res. 2015;21:5139–50.

    Article  CAS  Google Scholar 

  40. Lv P, Zhou M, He J, Meng W, Ma X, Dong S, et al. Circulating miR-208b and miR-34a are associated with left ventricular remodeling after acute myocardial infarction. Int J Mol Sci. 2014;15:5774–88.

    Article  CAS  Google Scholar 

  41. He J, Zhou M, Chen X, Yue D, Yang L, Qin G, et al. Inhibition of SALL4 reduces tumorigenicity involving epithelial-mesenchymal transition via Wnt/beta-catenin pathway in esophageal squamous cell carcinoma. J Exp Clin Cancer Res. 2016;35:98.

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by Science and Technology Commission of Shanghai Municipality (No. 15411952503) and National Nature Science Foundation of China (Nos. 81602326, 81741078, and 81801501).

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Author notes

  1. These authors contributed equally: **g He, Mingxia Zhou

Authors and Affiliations

  1. Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai, 200040, China

    **g He, **aoyan Li, Siwen Gu, Yun Cao, Tengfei **ng, Wei Chen, Chengyu Chu, Fei Gu, Jian Zhou, Yiting ** & Qiang Zou

  2. Department of Gastroenterology, **nhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai, 200092, China

    Mingxia Zhou

  3. Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Institute of Biomedical Sciences, Fudan University, 130 Dong’an Road, Shanghai, 200032, China

    **g Ma & Duan Ma

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Contributions

JH, MZ, DM, and QZ conceived and designed the experiments. XL, YC, SG, TX, WC, and CC collected clinical samples and patients’ information. JH, MZ, FG, and JZ performed animal experiments. JH, MZ, YJ, and JM analyzed the data and drafted the manuscript. DM and QZ supervised the study.

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Correspondence to Duan Ma or Qiang Zou.

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He, J., Zhou, M., Li, X. et al. SLC34A2 simultaneously promotes papillary thyroid carcinoma growth and invasion through distinct mechanisms. Oncogene 39, 2658–2675 (2020). https://doi.org/10.1038/s41388-020-1181-z

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