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Dec 20, 2012 - Proteome Atlas of Human Chromosome 8 and Its Multiple 8p. Deficiencies in Tumorigenesis of the Stomach, Colon, and Liver. Yang Zhang,...
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Proteome Atlas of Human Chromosome 8 and Its Multiple 8p Deficiencies in Tumorigenesis of the Stomach, Colon, and Liver Yang Zhang,†,○ Guoquan Yan,†,○ Linhui Zhai,‡,§,○ Shaohang Xu,∥,○ Huali Shen,† Jun Yao,† Feifei Wu,† Liqi Xie,† Hailin Tang,# Hongxiu Yu,† Mingqi Liu,† Pengyuan Yang,† Ping Xu,‡,§ Chengpu Zhang,‡,§ Liwei Li,‡,§ Cheng Chang,‡,§ Ning Li,‡,§ Songfeng Wu,‡,§ Yunping Zhu,‡,§ Quanhui Wang,∥,⊥ Bo Wen,∥ Liang Lin,∥ Yinzhu Wang,∥ Guiyan Zheng,∥ Lanping Zhou,□ Haojie Lu,*,† Siqi Liu,*,∥,⊥ Fuchu He,*,‡,§ and Fan Zhong*,† †

Institutes of Biomedical Sciences and Department of Chemistry, Fudan University, Shanghai 200032, China State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China § National Engineering Research Center for Protein Drugs, Beijing 102206, China ∥ BGI-Shenzhen, Shenzhen 518083, China ⊥ Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, China # College of Mechanical & Electronic Engineering and Automatization, National University of Defense Technology, Changsha 410073, China □ State Key Laboratory of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China ‡

S Supporting Information *

ABSTRACT: Chromosome 8, a medium-length euchromatic unit in humans that has an extraordinarily high mutation rate, can be detected not only in evolution but also in multiple mutant diseases, such as tumorigenesis, and further invasion/ metastasis. The Chromosome-Centric Human Proteome Project of China systematically profiles the proteomes of three digestive organs (i.e., stomach, colon, and liver) and their corresponding carcinoma tissues/cell lines according to a chromosome organizational roadmap. By rigorous standards, we have identified 271 (38.7%), 330 (47.1%), and 325 (46.4%) of 701 chromosome 8-coded proteins from stomach, colon, and liver samples, respectively, in Swiss-Prot and observed a total coverage rate of up to 58.9% by 413 identified proteins. Using large-scale label-free proteome quantitation, we also found some 8p deficiencies, such as the presence of 8p21−p23 in tumorigenesis of the above-described digestive organs, which is in good agreement with previous reports. To our best knowledge, this is the first study to have verified these 8p deficiencies at the proteome level, complementing genome and transcriptome data. KEYWORDS: chromosome 8, proteome, 8p deletion, tumorigenesis, liver, colon, stomach

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INTRODUCTION

Chromosome 8 is a medium-length euchromatic unit in humans that has an extraordinarily high mutation rate by positive selection.3,4 DEF5 and MCPH16,7 are widely known rapidly evolving gene clusters in 8p. Telomere shortening, especially in chromosome 8, appears as a mechanism fostering the development of chromosomal instability during aging and chronic disease.8 This relatively high genomic instability of chromosome 8 is found not only in evolution but also in

The Chromosome-Centric Human Proteome Project (C-HPP) has received considerable attention for its significance in understanding gene function and structure in terms of chromosome proteins.1,2 The International Human Genome Sequencing Consortium recently completed a sequence of the human genome including chromosome 8. It has reported a manually curated gene catalog, containing 793 gene loci and 301 pseudogene loci, including all previously known genes on chromosome 83 and giving 701 nonredundant proteins in Swiss-Prot (Version 2012-7-11). © 2012 American Chemical Society

Special Issue: Chromosome-centric Human Proteome Project Received: August 31, 2012 Published: December 20, 2012 81

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Figure 1. Chromosome 8 proteome atlas with data on the quantification (A) and identification (B) of gastric (green text and frame), colorectal (blue text and frame), and hepatic (red text and frame) systems. (A) The colors denote the abundance of the protein expression data. The median normalized protein data were transformed by log2 and rescaled into a [−1,1] region. The protein data above the median are shown in red, whereas those below the median are shown in blue. The color legend is provided at the top portion. (B) The protein coding genes are shown in blue.

information, is more robust for LTQ data. More details on proteome quantification are provided in the related article. The mass spectrum results detected rather high incidences of missing values (without identification in some replicates). Use of each proteomic experimental replicate as input column would disrupt further Gene Set Enrichment Analysis (GSEA) processing. To solve this problem, we calculated the average of SIN or LFQuant values for each sample as representation, rather than deal with each fluctuant experimental replicate in further analysis. For comparative analysis of liver samples, we further normalized SIN and LFQuant values by dividing their medians.

multiple mutant diseases, such as tumorigenesis, and further invasion/metastasis. Chromosome 8 and its 8p deletion have been studied and determined to be associated with hepatocellular carcinoma (HCC) metastasis for many years.9 As part of the Chinese C-HPP consortium, chromosomes 1, 8, and 20 have been selected to systematically profile the proteomes of three digestive organs, namely, stomach, colon, and liver, as well as their corresponding carcinoma tissues/cell lines. From the perspective of pathophysiological significance in China and worldwide, digestive cancers, such as gastric cancer (GC), colorectal cancer (CRC), and HCC, are among the most frequently reported cancers and are characterized by metastatic potential and poor outcomes. This digestive group includes some of the most critical cancers (among them are those ranked second to fourth in cancer-related mortality) and, despite all sustained efforts, maintains a profile of low survival rates and lacks successful therapies.10 Herein, we report the proteome of chromosome 8 based on measured proteins from samples of selected digestive tissues/cells and summarize the total nonredundant proteins reported so far for the said proteome. We also discuss the connections of measured 8p deletions with these three digestive cancers.

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Biological Category Statistics and Enrichment Analysis

“Data set Files” and “Analyses” under “Human Genes Chromosomal Location” in Ingenuity Pathway Analysis (IPA, Ingenuity Systems; www.ingenuity.com) Version 14197757 were used for cell, tissue, and organ (CTO) and cell line distribution statistics as well as biological category enrichment analysis. Enrichment analysis of 288 missing chromosome 8-coded proteins was carried out using the web-accessible Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool.14 DAVID can recognize the UniProt AC from data sets. Medium classification stringency and default items were chosen for enrichment calculation.

MATERIALS AND METHODS

Proteome Identification and Quantification

GSEA

Proteomes from 18 samples, namely, liver tissue11 Hep3B, SNU398, SNU449, SNU475, MHCC97L (97L), MHCC97H (97H), HCCLM3 (LM3), HCCLM6 (LM6), colon tissue, CRC tissue, SW480, HCT116, stomach tissue, GC tissue, AGS, BGC823, and SGC7901, were identified or researched as described in a companion article (DOI: 10.1021/pr3008286). Protein abundance in the human liver data set and that in 17 other samples were quantified by SIN12 and by LFQuant,13 respectively. Both are label-free proteome quantification methods, and the SIN method, which does not use XIC

GSEA15 was performed to find down-regulated enriched cytobands in chromosome 8. The data set was loaded from HUGO Gene Nomenclature Committee-approved gene symbols16 and analyzed using the Java GSEA package.17 We scanned (Signal2Noise metric, weighted scoring, 1,000 phenotype permutations) the cytoband-organized c1 gene sets of Molecular Signature Database v3.0. As GSEA requires at least three (sample) columns for each phenotype group, we replicated stomach, colon, and liver proteome data to appear 82

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Figure 2. Overlapping status of samples in total and chromosome 8-coded protein identifications. (A−C) Unique (diagonal, red text) and overlapped identification scales within gastric (A), colorectal (B), and hepatic (C) systems. Numbers of chromosome 8-coded proteins are given in brackets. (D−K) Venn diagrams comparing total proteins (D−F) and chromosome 8-coded proteins (G−I) identified within the three digestive systems and among three normal digestive organs (J, K). (L, M) Venn diagrams comparing total proteins (L) and chromosome 8-coded proteins (M) from the present study, PeptideAtlas, and MaxQB.

respectively, using rigorous standards. The proteomes from these samples provided 413 identified proteins in total and gave a total coverage of up to 58.9%. The total identification coverage of chromosome 8-coded proteins in other 5 databases were Ensembl (gene level, v.69) 402/696 = 57.8%, neXtProt (v.2012-10-16) 413/700 = 59.0% (Table S2 in Supporting Information), GPMdb (green, v.2012-10-18) 355/472 = 75.2%, Peptide Atlas (1% FDR at protein level, v.2012-07) 333/385 = 86.5%, and Human Protein Atla (v.10.0) 314/467 = 67.2%. These findings suggest that selections of any CTOs (Table S3 in Supporting Information) and cell lines (Table S4 in Supporting Information) seldom cover more than 50% of genes or those with expression bias in each chromosome. When the sample was limited to merely normal or paracancer tissues, these identification scales decreased to 112 (16.0%, stomach),

thrice as well as HCT116 and SW480 proteome data to appear twice for comparison. The gene sets with normalized enrichment scores lower than −1.00 were enriched in a down-regulated direction.

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RESULTS

Proteomes of the Three Digestive Organs

All proteome data sets for liver, stomach, and colon samples have been thoroughly discussed elsewhere for the proteome of chromosome 1 (see the companion article, DOI: 10.1021/ pr3008286). In brief, we identified 271 (38.7%), 330 (47.1%), and 325 (46.4%) of 701 chromosome 8-coded proteins in Swiss-Prot (Version 2012-7-11) from stomach, colon, and liver samples (Figure 1 and Table S1 in Supporting Information), 83

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Figure 3. 8p deficiencies in the three digestive organs by cancer versus normal pairing. (A) GSEA normalized enrichment score (NES) of chromosome 8 cytobands in cancer versus normal comparisons. The negative value indicates down-regulation, and |NES| > 1.00 can be significant. (B) Heatmaps of protein abundance located on 8p21−p23 in each sample are displayed based on the protein quantification values, leaving those unidentified as blank blocks. The color legend is shown on the right side of the heatmaps.

303 (43.2%, colon), and 238 (34.0%, liver). The 288 missing proteins of chromosome 8-coded proteins were found to be mostly enriched in the “disulfide bond, signal peptide, secreted, and glycoprotein” cluster (enrichment score = 3.45, p = 1.3 × 10−5, Benjamini = 7.7 × 10−3) and “defensin, antimicrobial, and defense response” cluster (enrichment score = 2.68, p = 9.0 × 10−4, Benjamini = 0.57) according to DAVID. IPA preanalysis showed no major expression bias of chromosomes among different CTOs (Table S3 in Supporting Information) and cell lines (Table S4 in Supporting Information) at the transcriptome level, thus answering the intriguing question of whether any expression bias exists as we select a sample for C-HPP profiling. These results also confirm that chromosome 8 is distinctly typical in character, being very close to the genome median for each characteristic in terms of length, gene content, repeat content, and segmentally duplicated fraction,3 although some chromosomes apparently exhibited extreme characteristics. There were 2 insufficient protein identified cytobands that 8p23.1 (52/288) and 8q24.3 (39/288), and the proteome quantification distribution among the 18 samples and their chromosome 8-coded subsets did not significantly differ (Figure S1 in Supporting Information). We observed that the overlap of proteomes was high between cancer and normal/paracancer tissues of the same organ and among cancer cell lines from the same organ but relatively low between tissues and cell lines (Figure 2A−F). A similar status was observed in chromosome 8-coded proteomes (Figure 2G−I). Not surprisingly, the proteome of the stomach was almost inclusive of that of the colon (3,254/3,375), mainly due to the similar compositions of these two organs from gastrointestinal epithelia (Figure 2J). Only two chromosome 8coded proteins were identified in the stomach, namely, IDO1 (8p11−p12) and NACAP1 (8q22.3), but these were not

detected in the colon (Figure 2K). We also compared our data set with published data sets for the whole proteome (Figure 2L) and the chromosome 8-coded proteome (Figure 2M). Aebersold et al.18 created a PeptideAtlas data set including 406 proteins of chromosome 8 among 12,173 proteins collected from the literature. In addition, a MaxQB data set with 313 proteins of chromosome 8 among 10,463 proteins measured from 11 cell lines was established by Mann et al.19 Altogether, these three data sets provide 487 nonredundant proteins and an increased coverage of 69.5% for the chromosome 8-coded proteome. 8p Deficiencies in Tumorigenesis

We performed GSEA based on quantified proteome data and found that multiple significantly down-regulated enriched cytobands existed in chromosome 8, especially 8p21−p23 of all three digestive organs (Figure 3A). Detailed heatmaps with cancer versus normal pairing showed that several 8p21−p23coded proteins (Figure 3B) were clearly down-regulated or absent and occurred in other cytobands of chromosome 8 (Figure S2 in Supporting Information). We determined that chromosome 8 exhibits the highest enrichment of breast cancer genes (p = 1.68 × 10−10) and orthologs to (mouse) mammary tumor genes (p = 2.23 × 10−10) (Table S5 in Supporting Information), as well as the highest coverage (32.0%) of tumorigenesis genes among all chromosomes (Table S6 in Supporting Information). Our proteome results for chromosome 8 seem to be in good agreement with the findings for the genome. Particularly, the proteins of some reported HCC, CRC, and GC suppressor genes in 8p, namely, CCDC25 (8p21.1),20 DLC1 (8p21.3−p22),20,21 EPHX2 (8p12−p21),20,22 LZTS1 (8p22),23 NRG1 (8p12−p21),24 PCM1 (8p22),25 PROSC 84

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Figure 4. Protein abundances located on 8p of HCC, CRC, and GC suppressor genes were down-regulated or deficient in the three carcinomatous digestive organs.

(8p11.2),20 SCARA5 (8p21.1),26 SH2D4A (8p21.2),20,27 SORBS3 (8pter−p23.3), 20,28 TUSC3 (8p22), 29 WRN (8p11.2−p12),24 and ZNF703 (8p12),24 were significantly down-regulated or deficient in the three carcinomatous digestive organs (Figure 4). Some proteins of HCC and CRC suppressor genes located in other cytobands were also found to be down-regulated/deficient, including BIRC2 (11q22);30 CA1 (8q13-q22.1), CA2 (8q22), and CA13 (8q21.2);31 CDH1 (16q22.1); TCF4 (18q21.2);32 TP53 (17p13); and YAP1 (11q13)30 (Figure S3 in Supporting Information).

the missing 214 proteins in chromosome 8 could be cellspecific proteins in cells other than those we have explored. Although each cell type might express a few tens of cell-specific proteins only, the total number of cell-specific proteins could be accumulated as the amount of measured cell type would increase. As such, we strongly suggest that more types of CTOs and cell lines be measured to observe all 701 possibly expressed proteins in chromosome 8, because the numbers of cell types in the present and previous studies are still considerably lower than the minimum possible of 230 for all cell types. We investigated some 8p deficiencies, such as the presence of 8p21−p23 in tumorigenesis of the stomach, colon, and liver. 8p11.21, 8p21.3, and 8p22−p23 losses and 8q24 gain frequently occurred in HCC tumorigenesis and its metastasis.9,34−37 8p deletions/LOH including 8p21, 8p22−23.1, and 8q24 gains also promoted CRC and its metastasis.24,32,38−41 The 8p deletion/LOH is also a frequent event in GC.42−45 8p contains many tumor suppressor genes and is essential for cancer progression and metastasis.45,46 In addition to HCC, CRC, and GC, 8p deletions can be found in lung cancer,47 larynx cancer,48 and renal cancer.49 8p LOH also occurs in bladder cancer,50,51 breast cancer,45−49,52 B cell lymphoma,53 prostate cancer,54−56 and head and neck squamous cell carcinoma.57,58 Particularly, loss of chromosome 8p associated with poor outcome (reduced survival time) and deletion of a cluster of six genes on 8p (CCDC25, DLC1, ELP3, PROSC, SH2D4A, and SORBS3) among the 10-gene signature in HCC from patients with poor outcomes have been reported.9,34 Thus, the deletion of chromosome 8p (e.g., 8p23) might contribute to the development of HCC metastasis.9 The 8p deletion/LOH in chromosome 8 can be attributed to its genome instability. The chromosome has a vast region of approximately 15 megabases on distal 8p with a strikingly high

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DISCUSSION Using the latest instruments and methodology in this study, we have determined that the identified proteins in each sample from the stomach, colon, and liver are less than or close to only half of the proteome (701) of chromosome 8. We thus speculated that the average of half of a chromosome proteome might be the upper limit for expressed proteins. Aebersold et al. provided a quantitative description of the proteome of a commonly used human cell line and demonstrated that the human cultured cells express at least approximately 10,000 proteins.33 This number is close to half of the total number of the protein-coded genome (∼20,344), which might explain why only approximately half of or fewer proteins on average can be found in chromosome 8 for a cell or several cells. Mann et al. identified 313 proteins belonging to chromosome 8 from 10,463 proteins in 11 cell lines, comparable with our 325 proteins from 8 cell lines and tissues from the liver (Figure 1I). PeptideAtlas has summarized 406 proteins of chromosome 8 among 12,173 proteins from literature data sources (cells and tissues) to date, and the present work study increases this number to 487 from a total of 16,079 proteins for the proteome of chromosome 8 (Figure 1L and M). Therefore, we feel that 85

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mutation rate, perhaps due to its high mutation rates in the human genome, proximity to telomeres, high recombination rate, and high A+T content in chromosome 8, although this biological basis remains unclear.3 This 8p deletion/LOH can be attributed to the telomere shortening correlated significantly with an increasing copy number of chromosome 8 at the cellular level and linked to a specific genetic alteration characteristic of human HCC based on an analysis of hepatocellular telomere fluorescent intensity and copy number of chromosome 8.8 In addition, we also doubt that dispersed proteins from multiple cells in a sample will be mixed together and weaken the 8p deletion in the proteome level. This may cause some proteins to exhibit down-regulation but not complete absence in carcinomatous samples. Nevertheless, we could conclude that a number of genes in the region of high divergence in distal 8p are essential to the development and metastasis of human digestion cancers.

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ASSOCIATED CONTENT

* Supporting Information Table S1 and S2 show the protein identification scales and coverage of each chromosome from all samples in Swissprot and neXtprot metrics, respectively. Tables S3 and S4 show the chromosome−CTO and cell line gene distributions from IPA, respectively. Table S5 lists the top chromosome-enriched biofunctions from IPA. Table S6 lists the top covered chromosomes in each biofunction from IPA. Figure S1 illustrates that the median normalized quants of all and chromosome 8-coded proteins from the 18 samples did not significantly differ. Figure S2 shows the heatmap of protein abundance located on chromosome 8 in each sample. Figure S3 demonstrates that the protein abundances of several HCC, CRC, and GC suppressor genes (other than those located on 8p) were down-regulated or deficient in the three carcinomatous digestive organs. These materials are available free of charge at http://pubs.acs.org.This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*(H.L.) Tel and Fax: +86 21 54237007. E-mail: luhaojie@ fudan.edu.cn. (S.L.) Tel and Fax: +86 10 80485324. E-mail: [email protected]. (F.H.) Tel and Fax: +86 10 68177417. Email: [email protected]. (F.Z.) Tel and Fax: +86 21 54237158. E-mail: [email protected]. Author Contributions ○

These authors contribute equally to this work.

Notes

The authors declare no competing financial interest.

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REFERENCES

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ACKNOWLEDGMENTS

The study was supported by MOST-S973/863 projects (2013CB910802, 2010CB912700, 2012CB910600, 2012AA020200, 2011CB910600, 2011CB910701, 2012AA020201, and 2012AA020206), National Natural Science Foundation of China projects (31000379, 21025519, 81201534, 31070673, 31170780, and 91131009), Shanghai Health Bureau Project (2010Y005), State Key Project Specialized for Infectious Diseases (2012ZX10002012−006). 86

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