The Effect Of Beclin 1, P53 Mutation, Ki-67 Proliferation İndex, Tumor Necrosis and Microvascular İnvasion On Prognosis İn Renal Cell Carcinomas and Their Relationship With Known Prognostic Parameters

Yıl 2021, , 241 - 250, 07.07.2021

İlke Evrim Seçinti , Egemen Akıncıoğlu , Olcay Kandemir

https://doi.org/10.17517/ksutfd.794679

Cited By: 1

Öz

Aim: The aim of this study was to help identify new prognostic markers in renal cell carcinomas (RCC), to show the role of autophagy in the pathogenesis of RCC and to shed light on new treatment modalities in RCC.
Material and Methods: Clinicopathological stages, tumor necrosis and microvascular invasion (MVI) were determined retrospectively and Beclin-1, Ki-67, and p53 were studied immunohistochemically.
Results: Tumor necrosis, MVI, Ki-67, and p53 in RCCs were positively correlated with Fuhrman nuclear grade and pathologic tumor stage, while Beclin-1 was only associated with nuclear grade. MVI and Ki-67 were associated with distant organ and lymph node metastasis. Ki-67 and necrosis correlated positively with p53 and Beclin-1 expression, but not with MVI. Beclin-1 were positively correlated necrosis, but not with p53 and MVI. p53, Ki-67 and MVI were negatively correlated with survival, while the effect of Beclin -1 and necrosis on survival couldn’t be demonstrated. Conclusion: Ki-67, p53, and MVI in RCCs are prognostic parameters with effects on survival. Although Beclin-1 was not a prognostic parameter associated with survival, its expression in tumor tissue was found to be increased. At the same time, there is less staining in non-tumor renal parenchyma. Beclin-1 is a marker of autophagy and is thought to be involved in RCC pathogenesis rather than its prognostic significance.

Anahtar Kelimeler

Renal cell carcinoma, autophagy, Beclin 1, Ki-67, p53

Beclin 1, P53 Mutasyonu, Ki-67 Proliferasyon İndeksi, Tümör Nekrozu ve Mikrovasküler İnvazyonun Böbrek Hücreli Karsinomlarda Prognoz Üzerindeki Etkisi ve Bunların Bilinen Prognostik Parametrelerle İlişkisi

Öz

Amaç: Bu çalışmanın amacı böbrek hücreli karsinomlarda (BHK) yeni prognostik belirteçlerin belirlenmesine yardımcı olmak, otofajinin BHK patogenezindeki rolünü göstermek ve BHK'daki yeni tedavi yöntemlerine ışık tutmaktır.
Gereç ve Yöntemler: Klinikopatolojik evreler, tümör nekrozu ve mikrovasküler invazyon (MVI) retrospektif olarak belirlendi ve Beclin-1, Ki-67 ve p53 immünohistokimyasal olarak incelendi.
Bulgular: BHK’larında tümör nekrozu, MVI, Ki-67 ve p53; Fuhrman nükleer derece ve patolojik tümör evresi ile pozitif korelasyon gösterirken, Beclin-1 sadece nükleer derece ile ilişkiliydi. MVI ve Ki-67, uzak organ ve lenf nodu metastazı ile ilişkiliydi. Ki-67 ve nekroz, p53 ve Beclin-1 ekspresyonu ile pozitif koreleydi ancak MVI ile korele değildi. Beclin-1 nekroz ile koreleydi, ancak p53 ve MVI ile korele değildi. p53, Ki-67 ve MVI sağkalım ile negatif korelasyon gösterirken Beclin -1 ve nekrozun sağkalım üzerindeki etkisi gösterilemedi.
Sonuç: BHK’larda Ki-67, p53 ve MVI sağkalım üzerine etkileri olan prognostik parametrelerdir. Beclin-1, sağkalım ile ilişkili bir prognostik parametre olmamasına rağmen, tümör dokusunda ekspresyonunun arttığı bulundu. Aynı zamanda, tümör dışı böbrek parankiminde daha az boyama vardır. Beclin-1, otofajinin bir belirtecidir ve prognostik öneminden ziyade BHK patogenezinde rol oynadığı düşünülmektedir.

Anahtar Kelimeler

Böbrek hücreli karsinom, otofaji, , Beclin 1, Ki-67, p53

Kaynakça

• 1- Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.1, Cancer Incidence and Mortality Worldwide: IARC CancerBase No.11. Lyon, France: International Agency for Research on Cancer; 2014. Available from: http://globocan.iarc.fr, accessed on 12.09.2018.
• 2- Srigley JR, Zhou M, Allan R, Amin MB, Campbell SC, Chang A, et al. Protocol for the Examination of Specimens from Patients with Invasive Carcinoma of Renal Tubular Origin. College of American Pathologists (CAP). 2017.
• 3- Lang H, Lindner V, Letourneux H, Martin M, Saussine C, Jacqmin D. Prognostic value of microscopic venous invasion in renal cell carcinoma: long-term follow-up. Eur Urol. 2004; 46: 331–335.
• 4- Delahunt B, Cheville JC, Martignoni G, Humphrey PA, Magi-Galluzzi C, McKenney J, et al. Members of the ISUP Renal Tumor Panel. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol. 2013; 37: 1490-1504.
• 5- Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol. 2003; 27: 612–624.
• 6- Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin. 2013;63:11-30.
• 7- Hu Y. Jahangiri A, Delay M, and Aghi MK. Tumor cell autophagy as an adaptive response mediating resistance to treatments such as antiangiogenic therapy. Cancer Res. 2012; 72: 4294–4299.
• 8- Chen N and Debnath J. Autophagy and tumorigenesis. FEBS Lett. 2010; 584: 1427–1435.
• 9- Kumar V, Abbas AK and Aster AJ. The Cellular Responses to Stress and Toxic Insults: Adaptation, Injury, and Death, Robbins and Cotran Pathologic Basis of Disease Ninth Edition (p.60-61). Philadelphia: Elsevier. 2015.
• 10- Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009; 20: 1992–2003.
• 11- Noda T, Fujita N, Yoshimori T. The late stages of autophagy: how does the end begin? Cell Death Differ. 2009; 16: 984-990.
• 12- Tasdemir E, Galluzzi L, Maiuri MC, Criollo A, Hangen E, Modjtahedi N, et al. Methods for assessing autophagy and autophagic cell death. Methods Mol Biol. 2008; 445: 29-76.
• 13- Chen Y and Yu L. Autophagic lysosome reformation. Exp Cell Res. 2013; 319: 142-146.
• 14- Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999; 402: 672–676.
• 15- Galluzzi L, Morselli E, Vicencio JM, Kepp O, Joza N, Tajeddine N, et al. Life, death and burial: multifaceted impact of autophagy. Biochem. Soc. Trans. 2008; 36: 786–790.
• 16- Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003; 112: 1809–20.
• 17- Cully M, You H, Levine AJ, Mak TW. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis, Nat. Rev. Cancer. 2006; 6: 184–92.
• 18- Ciechomska IA, Goemans GC, Skepper JN, Tolkovsky AM. Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function. Oncogene. 2009; 28: 2128–41.
• 19- Morselli E, Galluzzi L, Kepp O, Vicencio JM, Criollo A, Maiuri MC, et al. Anti- and pro-tumor functions of autophagy. Biochim Biophys Acta Mol Cell Res. 2009; 1793: 1524–32.
• 20- Tasdemir E, Maiuri MC, Galluzi L, Vitale I, Djavaheri-Mergny M, D'Amelio M. et al. Regulation of autophagy by cytoplasmic p53. Nat Cell Biol. 2008; 10: 676–87.
• 21- Nikoletopoulou V, Markaki M, Palikaras K and Tavernarakis N. Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta Mol Cell Res. 2013; 1833: 3448–59.
• 22- Gerdes J. Ki-67 and other proliferation markers useful for immunohistological diagnostic and prognostic evaluations in human malignancies. Semin Cancer Biol. 1990; 1: 199-206.
• 23- Zhang L, Zha Z, Qu W, Zhao H, Yuan J, Yejun Feng, et al. Tumor necrosis as a prognostic variable for the clinical outcome in patients with renal cell carcinoma: a systematic review and meta-analysis. BMC Cancer. 2018; 18: 870.
• 24- Delahunt B, McKenney JK, Lohse CM, Leibovich BC, Thompson RH, Boorjian SA, et al. A novel grading system for clear cell renal cell carcinoma incorporating tumor necrosis. Am J Surg Pathol. 2013; 37: 311–22.
• 25- Kirkali Z, Lekili M. Renal cell carcinoma: new prognostic factors? Curr Opin Urol. 2003; 13: 433-38.
• 26- Kwon SY, Lee JN, Kim BS, Ko YH, Song PH, Kim HT, et al. Impact of Microvascular Invasion and Tumor Necrosis on the Prognosis of Korean Patients with pT1b Renal Cell Carcinoma. Urol Int. 2015; 95: 65–71.
• 27- Bedke J, Heide J, Ribback S, Rausch S, de Martino M, Scharpf M, et al. Microvascular and lymphovascular tumor invasion are associated with poor prognosis and metastatic spread in renal cell carcinoma: a validation study in clinical practice. BJU Int. 2018; 121: 84-92.
• 28- Rioux-Leclercq N, Turlin B, Bansard J, Patard J, Manunta A, Moulinoux JP, et al. Value of immunohistochemical Ki-67 and p53 determinations as predictive factors of outcome in renal cell carcinoma. Urology. 2000; 55: 501–505.
• 29- Yuba H, Okamura K, Ono Y, Ohshima S. Growth Fractions of human renal cell carcinoma defined by monoclonal antibody Ki-67. Predictive values for prognosis. Int J Urol. 2001; 8: 609-14.
• 30- Oda T, Takahashi A, Miyano N, Yanase M, Masumori N, Itoh N, et al. Cell proliferation, apoptosis, angiogenesis and growth rate of incidentally found renal cell carcinoma. Int J Urol. 2003; 10: 13-18.
• 31- Haitel A, Wiener HG, Migschitz B, Marberger M, Susani M. Proliferating cell nuclear antigen and MIB-1. An alternative to classic prognostic indicators in renal cell carcinomas? Am J Clin Pathol. 1997; 107: 229-35.
• 32- Cheville JC, Zincke H, Lohse CM, Sebo TJ, Riehle D, Weaver Al, et al. pT1 clear cell renal cell carcinoma: a study of the association between MIB-1 proliferative activity and pathologic features and cancer specific survival. Cancer. 2002; 94: 2180-4.
• 33- Kramer BA, Gao X, Davis M, Hall M, Holzbeierlein J, Tawfik O. Prognostic significance of ploidy, MIB-1 proliferation marker, and p53 in renal cell carcinoma. J Am Coll Surg. 2005; 30: 565-70.
• 34- Uchida T, Gao JP, Wang C, Jiang SX, Muramoto M, Satoh T, et al. Clinical significance of p53, mdm2, and bcl-2 proteins in renal cell carcinoma. Urology. 2002; 59: 615-20.
• 35- Noon AP, Polański R, El-Fert AY, Kalirai H, Shawki H, Campbell F, et al. Combined p53 and MDM2 biomarker analysis shows a unique pattern of expression associated with poor prognosis in patients with renal cell carcinoma undergoing radical nephrectomy. BJU Int. 2012; 109: 1250-7.
• 36- Dijkhuizen T, Van den Berg E, Van den Berg A, Störkel S, De Jong B, Seitz G, et al. Chromosomal findings and p53 mutation analysis in chromophilic renal cell carcinomas. Int J Cancer.1996; 68: 47-50.
• 37- Hodorova I, Solar P, Mihalik J, Vecanova J, Adamkov M, Rybarova S. Investigation of tumour supressor protein p53 in renal cell carcinoma patients. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014; 158: 44-9.
• 38- Warburton HE, Brady M, Vlatković N, Linehan WM, Parsons K, Boyd MT. p53 regulation and function in renal cell carcinoma. Cancer Res. 2005; 65: 6498-503.
• 39- Amaravadi RK, Lippincott-Schwartz J, Yin XM, Yin XM, Weiss WA, Takebe N, et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res. 2011; 17: 654-66.
• 40- Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 2006; 10: 51–64.
• 41- Lee YJ, Ha YJ, Kang YN, Kang KJ, Hwang JS, Chung WJ, et al.The autophagy-related marker LC3 can predict prognosis in human hepatocellular carcinoma. PLoS One. 2013; 8: e81540.
• 42- Wan XB, Fan XJ, Chen MY, Xiang J, Huang PY, Guo L, et al. Elevated Beclin 1 expression is correlated with HIF-1alpha in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy. 2010; 6: 395–404.
• 43- Qiu DM, Wang GL, Chen L, Xu YY, He S, Cao XL, et al. The expression of beclin-1, an autophagic gene, in hepatocellular carcinoma associated with clinical pathological and prognostic signifcance. BMC Cancer. 2014; 14: 327.
• 44- Zheng T, Lİ D, He Z, Feng S, Zhao S. Prognostic and clinicopathological signifcance of Beclin-1 in non-small-cell lung cancer: a meta-analysis. OncoTargets and Terapy. 2018; 11: 4167–75.
• 45- Turcotte S, Chan DA, Sutphin PD, Hay MP, Denny WA, Giaccia AJ. A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell. 2008; 14: 90–102.
• 46- Wang ZL, Deng QD, Chong T and Wang ZM. Autophagy suppresses the proliferation of renal carcinoma cell. Eur Rev Med Pharmacol Sci. 2018; 22: 343-50.
• 47- Deng Q, Wang Z, Wang L, Zhang L, Xiang X, Wang Z, et al. Lower mRNA and Protein Expression Levels of LC3 and Beclin1, Markers of Autophagy, were Correlated with Progression of Renal Clear Cell Carcinoma. Jpn J Clin Oncol. 2013; 43: 1261–8.
• 48- Nishikawa M, Miyake H, Liu B and Fujisawa M. Expression pattern of autophagy-related markers in non-metastatic clear cell renal cell carcinoma: association with disease recurrence following radical nephrectomy. J Cancer Res Clin Oncol. 2015; 141: 1585-91.
• 49- Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 2007; 21: 1367–81.
• 50- Kang KF, Wang XW, Chen XW, Kang ZJ, Zhang X,Wilbur RR, et al. Beclin 1 and nuclear factor Bp65 are upregulated in hepatocellular carcinoma. Oncol Lett. 2013; 5: 1813–8.