Analysis of the characteristics of chemotherapy-resistant renal cell carcinomas based on global transcriptional analysis of their tissues and cell lines

Autoři: Takahiro Isono aff001;  Masafumi Suzaki aff001
Působiště autorů: Central Research Laboratory, Shiga University of Medical Science, Otsu, Shiga, Japan aff001
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225721


Starvation-resistant renal cell carcinoma (RCC) cell lines are considered dormant-state cells that survive even under glucose starvation. The cellular biological and global transcriptional analysis using these cells identified potential markers of chemotherapy-resistant RCC and therapeutic agent candidates. Recently, we showed that ARL4C was a predictive biomarker for poor prognosis in patients with chemotherapy-resistant RCC by the global transcriptional analysis of patient primary tissues. The objective of this study was to identify the characteristics of chemotherapy-resistant RCC by the global transcriptional analysis of primary tissues of patients with RCC and RCC cell lines. The connective global transcriptional analysis showed that two starvation-resistant RCC cell lines, SW839 and KMRC-1, were strongly correlated to tissues of patients with chemotherapy-resistant RCC and showed high expressions of invasive- and proliferation-related genes. We found fibronectin (FN1) expression was a predictive biomarker in some patients with chemotherapy-resistant RCC, which especially correlated with two starvation-resistant RCC cell lines. These results indicate these cell lines emulate chemotherapy-resistant RCC and might be useful in the search for markers to predict poor prognosis and in the development of therapeutic agents and their index markers for chemotherapy-resistant RCCs.

Klíčová slova:

Biomarkers – Cancer detection and diagnosis – Chemotherapeutic agents – Metastasis – Prognosis – Renal cell carcinoma – Surgical resection – TGF-beta signaling cascade


1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018; 68: 7–30. doi: 10.3322/caac.21442 29313949

2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136(5): E359–386. doi: 10.1002/ijc.29210 25220842

3. Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, et al. EAU guidelines on renal cell carcinoma 2014 update. Eur Urol. 2015; 67: 913–924. doi: 10.1016/j.eururo.2015.01.005 25616710

4. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007; 356: 125–134. doi: 10.1056/NEJMoa060655 17215530

5. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal cell carcinoma. N Engl J Med. 2007; 356: 115–124. doi: 10.1056/NEJMoa065044 17215529

6. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007; 370: 2103–2111. doi: 10.1016/S0140-6736(07)61904-7 18156031

7. Rixe O, Bukowski RM, Michaelson MD, Wilding G, Hudes GR, Bolte O, et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol. 2007; 8: 975–984. doi: 10.1016/S1470-2045(07)70285-1 17959415

8. Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, et al. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010; 28: 475–480. doi: 10.1200/JCO.2008.21.6994 20008644

9. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007; 356: 2271–2281. doi: 10.1056/NEJMoa066838 17538086

10. Isono T, Chano T, Kitamura A, Yuasa T. Glucose deprivation induces G2/M transition-arrest and cell death in N-GlcNAc2-modified protein-producing renal carcinoma cells. PLoS One. 2014; 9: e96168. doi: 10.1371/journal.pone.0096168 24796485

11. Isono T, Chano T, Yonese J, Yuasa T. Therapeutic inhibition of mitochondrial function induces cell death in starvation-resistant renal cell carcinomas. Sci Rep. 2016; 6: e25669. doi: 10.1038/srep25669 27157976

12. Isono T, Chano T, Yoshida T, Kageyama S, Kawauchi A, Yonese J, et al. Abundance of TRAIL attenuated by HIF2α and c-FLIP affects prognosis in malignant renal cell carcinomas. Oncotarget. 2018; 9: 23091–23101. doi: 10.18632/oncotarget.25214 29796174

13. Isono T, Chano T, Yoshida T, Kageyama S, Kawauchi A, Suzaki M, et al. Hydroxyl-HIF2-alpha is potential therapeutic target for renal cell carcinomas. Am J Cancer Res. 2016; 6: 2263–2276. 27822416

14. Isono T, Chano T, Yoshida T, Makino A, Ishida S, Suzaki M, et al. ADP-ribosylation factor-like 4C is a predictive biomarker of poor prognosis in patients with renal cell carcinoma. Am J Cancer Res. 2019; 9: 415–423. 30906638

15. Martin M. Cutadapt removes adapter sequences from high through put sequencing reads. EMB Net J. 2011;17: 10–12.

16. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14: R36. doi: 10.1186/gb-2013-14-4-r36 23618408

17. Trapnell C, Williams B, Pertea G, Mortazavi A, Kwan G, van Baren MJ, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nature Biotech. 2010; 28: 511–515. doi: 10.1038/nbt.1621 20436464

18. Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protoc. 2009; 4: 44–57. doi: 10.1038/nprot.2008.211 19131956

19. Steffens S, Schrader AJ, Vetter G, Eggers H, Blasig H, Becker J, et al. Fibronectin 1 protein expression in clear cell renal cell carcinoma. Oncol. Lett. 2012; 3: 787–790. doi: 10.3892/ol.2012.566 22740994

20. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018; 378: 1277–1290. doi: 10.1056/NEJMoa1712126 29562145

Článek vyšel v časopise


2019 Číslo 11