Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a tissue biomarker for detection of early Hepatocellular carcinoma in patients with cirrhosis

Journal of Hematology & Oncology

Quanyou Lai¹  Xin Wang¹  Quan Wu¹  Jingtao Bi¹  Jingming Zhao¹  Yantong Guo¹ 

[1] Department of Surgery, Beijing Jishuitan Hospital, the Fourth Clinical Medical College of Peking University, 31 Xinjiekou East Street, Xicheng District, Beijing, 100035, China

关键词: Biomarker;    Diagnosis;    Mass spectrometry;    Two-dimensional gel electrophoresis;    Proteome;    Hepatocellular carcinoma;   

Others  :  822353
DOI  :  10.1186/1756-8722-5-37

 received in 2012-04-29, accepted in 2012-06-19,  发布年份 2012

【 摘 要 】

Background

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors occurring mainly in patients with chronic liver disease. Detection of early HCC is critically important for treatment of these patients.

Methods

We employed a proteomic profiling approach to identify potential biomarker for early HCC detection. Based on Barcelona Clinic Liver Cancer (BCLC) staging classification, 15 early HCC and 25 late HCC tissue samples from post-operative HCC patients and their clinicopathological data were used for the discovery of biomarkers specific for the detection of early HCC. Differential proteins among cirrhotic, early, and late tissue samples were separated by two-dimensional gel electrophoresis (2-DE) and subsequently identified by mass spectrometry (MS). Receiver operating characteristic (ROC) curves analysis were performed to find potential biomarkers associated with early HCC. Diagnosis performance of the biomarker was obtained from diagnosis test.

Results

Protein spot SSP2215 was found to be significantly overexpressed in HCC, particularly in early HCC, and identified as heterogeneous nuclear ribonucleoprotein K (hnRNP K) by tandem mass spectrometry (MALDI TOF/TOF). The overexpression in HCC was subsequently validated by western blot and immunohistochemistry. ROC curve analysis showed that hnRNP K intensity could detect early HCC at 66.67 % sensitivity and 84 % specificity, which was superior to serum α-fetoprotein (AFP) in detection of early HCC. Furthermore, the diagnosis test demonstrated, when combined with hnRNP K and serum AFP as biomarker panel to detect early HCC at different cut-off value, the sensitivity and specificity could be enhanced to 93.33 % and 96 %, respectively.

Conclusions

hnRNP K is a potential tissue biomarker, either alone or in combination with serum AFP, for detection of early HCC. High expression of hnRNP K could be helpful to discriminate early HCC from a nonmalignant nodule, especially for patients with liver cirrhosis.

【 授权许可】

   
2012 Guo et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Bosch FX, Ribes J, Cleries R, Diaz M: Epidemiology of hepatocellular carcinoma. Clin Liver Dis 2005, 9:191-211. v.
• [2]Rabe C, Pilz T, Klostermann C, Berna M, Schild HH, Sauerbruch T, Caselmann WH: Clinical characteristics and outcome of a cohort of 101 patients with hepatocellular carcinoma. World J Gastroenterol 2001, 7:208-215.
• [3]Bruix J, Llovet JM: Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002, 35:519-524.
• [4]Gebo KA, Chander G, Jenckes MW, Ghanem KG, Herlong HF, Torbenson MS, El-Kamary SS, Bass EB: Screening tests for hepatocellular carcinoma in patients with chronic hepatitis C: a systematic review. Hepatology 2002, 36:S84-S92.
• [5]Bruix J, Sherman M: Management of hepatocellular carcinoma. Hepatology 2005, 42:1208-1236.
• [6]Sherman M: Alphafetoprotein: an obituary. J Hepatol 2001, 34:603-605.
• [7]Daniele B, Bencivenga A, Megna AS, Tinessa V: Alpha-fetoprotein and ultrasonography screening for hepatocellular carcinoma. Gastroenterology 2004, 127:S108-S112.
• [8]Rapaccini GL, Pompili M, Caturelli E, Covino M, Lippi ME, Beccaria S, Cedrone A, Riccardi L, Siena DA, Gasbarrini G: Hepatocellular carcinomas <2 cm in diameter complicating cirrhosis: ultrasound and clinical features in 153 consecutive patients. Liver Int 2004, 24:124-130.
• [9]Oka H, Tamori A, Kuroki T, Kobayashi K, Yamamoto S: Prospective study of alpha-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology 1994, 19:61-66.
• [10]Ishii M, Gama H, Chida N, Ueno Y, Shinzawa H, Takagi T, Toyota T, Takahashi T, Kasukawa R: Simultaneous measurements of serum alpha-fetoprotein and protein induced by vitamin K absence for detecting hepatocellular carcinoma. South Tohoku District Study Group. Am J Gastroenterol 2000, 95:1036-1040.
• [11]Kondo T: Tissue proteomics for cancer biomarker development: laser microdissection and 2D-DIGE. BMB Rep 2008, 41:626-634.
• [12]Elrick MM, Walgren JL, Mitchell MD, Thompson DC: Proteomics: recent applications and new technologies. Basic Clin Pharmacol Toxicol 2006, 98:432-441.
• [13]Befeler AS, Di Bisceglie AM: Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 2002, 122:1609-1619.
• [14]Llovet JM, Burroughs A, Bruix J: Hepatocellular carcinoma. Lancet 2003, 362:1907-1917.
• [15]Sasse EA: Objective evaluation of data in screening for disease. Clin Chim Acta 2002, 315:17-30.
• [16]Feng JT, Liu YK, Song HY, Dai Z, Qin LX, Almofti MR, Fang CY, Lu HJ, Yang PY, Tang ZY: Heat-shock protein 27: a potential biomarker for hepatocellular carcinoma identified by serum proteome analysis. Proteomics 2005, 5:4581-4588.
• [17]Yi X, Luk JM, Lee NP, Peng J, Leng X, Guan XY, Lau GK, Beretta L, Fan ST: Association of mortalin (HSPA9) with liver cancer metastasis and prediction for early tumor recurrence. Mol Cell Proteomics 2008, 7:315-325.
• [18]Michael WM, Eder PS, Dreyfuss G: The K nuclear shuttling domain: a novel signal for nuclear import and nuclear export in the hnRNP K protein. EMBO J 1997, 16:3587-3598.
• [19]Carpenter B, MacKay C, Alnabulsi A, MacKay M, Telfer C, Melvin WT, Murray GI: The roles of heterogeneous nuclear ribonucleoproteins in tumour development and progression. Biochim Biophys Acta 2006, 1765:85-100.
• [20]Michelotti EF, Tomonaga T, Krutzsch H, Levens D: Cellular nucleic acid binding protein regulates the CT element of the human c-myc protooncogene. J Biol Chem 1995, 270:9494-9499.
• [21]Tomonaga T, Michelotti GA, Libutti D, Uy A, Sauer B, Levens D: Unrestraining genetic processes with a protein-DNA hinge. Mol Cell 1998, 1:759-764.
• [22]Moumen A, Masterson P, O'Connor MJ, Jackson SP: hnRNP K: an HDM2 target and transcriptional coactivator of p53 in response to DNA damage. Cell 2005, 123:1065-1078.
• [23]Ng LF, Chan M, Chan SH, Cheng PC, Leung EH, Chen WN, Ren EC: Host heterogeneous ribonucleoprotein K (hnRNP K) as a potential target to suppress hepatitis B virus replication. PLoS Med 2005, 2:e163.
• [24]Ostrowski J, Bomsztyk K: Nuclear shift of hnRNP K protein in neoplasms and other states of enhanced cell proliferation. Br J Cancer 2003, 89:1493-1501.
• [25]Hsieh TY, Matsumoto M, Chou HC, Schneider R, Hwang SB, Lee AS, Lai MM: Hepatitis C virus core protein interacts with heterogeneous nuclear ribonucleoprotein K. J Biol Chem 1998, 273:17651-17659.
• [26]Barboro P, Repaci E, Rubagotti A, Salvi S, Boccardo S, Spina B, Truini M, Introini C, Puppo P, Ferrari N, Carmignani G, Boccardo F, Balbi C: Heterogeneous nuclear ribonucleoprotein K: altered pattern of expression associated with diagnosis and prognosis of prostate cancer. Br J Cancer 2009, 100:1608-1616.
• [27]Zhou R, Shanas R, Nelson MA, Bhattacharyya A, Shi J: Increased expression of the heterogeneous nuclear ribonucleoprotein K in pancreatic cancer and its association with the mutant p53. Int J Cancer , 126:395-404.
• [28]Carpenter B, McKay M, Dundas SR, Lawrie LC, Telfer C, Murray GI: Heterogeneous nuclear ribonucleoprotein K is over expressed, aberrantly localised and is associated with poor prognosis in colorectal cancer. Br J Cancer 2006, 95:921-927.