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(ZNF306) Is a Novel ''Driver'' of Colorectal Cancer Progression

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(ZNF306) Is a Novel ''Driver'' of Colorectal Cancer Progression Research Article The Previously Undescribed ZKSCAN3 (ZNF306) Is a Novel ‘‘Driver’’ of Colorectal Cancer Progression Lin Yang,1 Stanley R. Hamilton,2 Anil Sood,4 Toshio Kuwai,1 Lee Ellis,3 Angela Sanguino,1 Gabriel Lopez-Berestein,4 and Douglas D. Boyd1 Departments of 1Cancer Biology, 2Pathology, 3Surgical Oncology, and 4Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas Abstract growth via the mitogen-activated protein kinase (MAPK) pathway. Conversely, mutation of the type II transforming growth factor-h A relatively new view of colorectal cancer is that its b development/progression reflects the contribution of a large receptor gene (TGF- RII), yielding a truncated protein, disables set of altered gene products in varying combinations, each signaling through the MADH-encoded Smad transcription factors providing a ‘‘fitness advantage.’’ In searching for novel (5), thus failing to restrain growth. Paradoxically, this pathway also contributing gene products using Unigene cluster data contributes to tumor progression (6). In the p53 pathway, mutation mining, we found overrepresentation of expressed sequence inactivation of the tumor suppressor renders damaged cells unable tags corresponding to a previously uncharacterized gene to arrest for DNA repair and these cells are not eliminated by (ZKSCAN3) in colorectal tumors. ZKSCAN3 was pursued for apoptosis (7), leading to accumulated DNA damage and mutation of several reasons: (a) its sequence similarity with bowl required key genes crucial to tumor development/progression. for Drosophila hindgut development; (b) it lies in a chro- Notwithstanding these landmark observations, whereas the aforementioned encoded products are clearly implicated in mosomal region (6p22.1) amplified in colorectal cancer; colorectal pathogenesis, emerging studies suggest that the hetero- and (c) its coding sequence predicts tandem C2H2 zinc finger domains present in a class of proteins gaining attention for geneity of this disease probably also involves the contribution of their role in oncogenesis/tumor progression. Reverse tran- multiple other gene products (8, 9) acting in various combinations scription-PCR confirmed overexpression in colorectal tumor to promote cancer development and progression. For example, an tissue compared with adjacent nonmalignant mucosa due in analysis of 340 serine/threonine kinases revealed that 40% of part to gene amplification determined by Southern blotting. colorectal tumors had alterations of genes in the MAPK kinase/ Further, immunohistochemistry with an antibody generated c-jun amino-terminal kinase kinase 1 and phosphatidylinositol to the predicted protein sequence revealed higher ZKSCAN3 3-kinase (PI3K) pathways (10). The functional consequence of at expression in invasive compared with noninvasive tumors. least of one of these mutations in PI3KCA (encoding the catalytic Intriguingly, the ZKSCAN3 protein was also expressed in subunit of PI3K) was a reduced dependence on growth factors, tumors wild-type for genes (APC, p53, K-Ras) commonly attenuated apoptosis, and augmented tumor invasion (11). targeted in colorectal cancer. ZKSCAN3 knockdown in two Additionally, two independent genome-wide scans identified a novel, low-penetrance colorectal cancer susceptibility locus at independent colon cancer cell lines impaired anchorage- independent growth and orthotopic tumor growth, whereas chromosome 8q24 containing an uncharacterized gene (9, 12). overexpression in a third cell line had the opposite effect and Indeed, on analyzing the coding regions of some 18,191 genes, Wood increased 5-fluorouracil resistance. Liposomal delivery of a and coworkers (8) concluded that the genomic landscape of ZKSCAN3-targeting small interfering RNA reduced tumorige- colorectal cancer is composed of a few commonly targeted gene nicity of orthotopic colon cancer. Thus, the hitherto unchar- ‘‘mountains’’ with a much larger number of gene ‘‘hills’’ altered at acterized ZKSCAN3 adds to an expanding set of encoded low frequency, emphasizing the heterogeneity and complexity of products contributing to the progression of colorectal cancer. this disease. These findings, together with the observations that mice mutated (13–15) for some of the genes (p53, K-Ras, TGF-b RII) [Cancer Res 2008;68(11):4321–30] commonly targeted in this disease rarely develop colorectal cancer and that Li-Fraumeni patients defective for p53 fail to show a higher Introduction colorectal cancer incidence (16), have led investigators to propose Sporadic colorectal cancer, afflicting 145,000 persons per year in that multiple gene products, acting in various combinations, the United States (1), largely reflects aberrantly activated pathways contribute to colorectal cancer development/progression. In a leading to unrestrained growth. In the Wnt pathway, APC search for other ‘‘drivers’’ of colorectal cancer progression, we have truncations stabilize h-catenin, which translocates to the nucleus, identified ZKSCAN3, related to brother of odd with entrails limited and with T-cell factor-4 (TCF-4) and lymphoid enhancer factor-1 (bowl) required for Drosophila hindgut development (17) as a novel (LEF1) DNA-binding proteins (2) trans-activate target genes (3) gene product promoting the progression of this malignancy. causal for growth. Mutation-activated K-Ras (4) also promotes tumor Materials and Methods Unigene cluster analysis. ZKSCAN3 expressed sequence tag (EST) Requests for reprints: Douglas Boyd, Department of Cancer Biology, Box 173, overrepresentation, as determined by Unigene Cluster analysis,5 is as M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-4918; Fax: 713-563-5489; E-mail: [email protected]. I2008 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-08-0407 5 http://www.ncbi.nlm.nih.gov/sites/entrez?db=unigene www.aacrjournals.org 4321 Cancer Res 2008; 68: (11). June 1, 2008 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2008 American Association for Cancer Research. Cancer Research follows. The approximate frequency of a Unigene cluster occurrence previously (18). All experiments were approved by the Institutional Animal within each tissue is calculated6 as follows: A = B / C, where A is the Care and Use Committee. frequency of the Unigene cluster expression within the tissue, B is the Liposomal encapsulation of ZKSCAN3 (ZNF306)–targeting small number of Unigene clustered clones within the tissue, and C is the total interfering RNA. Small interfering RNA (siRNA) sequences were number of unique clones from the same tissue in the Unigene database. 5¶-AATATCGTGCCACCTGAGAGA-3¶ and 5¶-AATTCTCCGAACG-TG- ... The frequencies within each tissue are summed (D = A1 + A2 + A3 + ) TCACGT-3¶ as ZKSCAN3-targeting and control siRNA, respectively. siRNAs to find the total expression within Unigene, where D is the summation were dissolved in buffer [100 mmol/L potassium acetate, 30 mmol/L HEPES of Unigene cluster expression frequencies by tissue and A1, A2, A3, etc., is KOH, 2 mmol/L magnesium acetate (pH 7.4)] to a final concentration of the frequency of Unigene cluster expression in tissue 1, 2, 3, etc., 1 Ag/AL, heated to 90jC for 60 s, and incubated at 37jC for 60 min. respectively. Normalized Unigene cluster expression within a tissue is Liposome preparation for in vivo delivery was as previously described (19). derived by dividing the frequency of the Unigene cluster occurrence in a Briefly, siRNA and 1,2-dioleoyl-sn-glycero-3-phosphocholine (Avanti) at a tissue by the summation of Unigene cluster expression frequencies by ratio of 1:10 (w/w) and Tween 20 were mixed in the presence of excess tissue (i.e., A/D). t-butanol (Sigma); vortexed; frozen in an acetone, dry ice bath; and finally Reverse transcription-PCR analysis of resected colorectal cancers. lyophilized. Lyophilized liposomes were stored À20jC until needed. Before Total RNA was prepared from colorectal tissue (50 mg) in TRIzol administration, they were hydrated with normal (0.9%) saline. (Invitrogen) according to the manufacturer’s protocol. RNA (20 Ag) was Metastases model. Viable tumor cells (106 in 0.1 mL HBSS) were treated (37jC, 25 min) with 2 units/AL TURBO DNA-free DNase enzyme injected into the exteriorized spleen. After 6 wk, the mice were killed and (Ambion), and after DNase inactivation, cDNA was synthesized with avian the presence of liver disease was determined. myeloblastosis virus reverse transcriptase. PCR was done using primers Southern blotting. Southern blotting was done as described by us for ZKSCAN3 [100 ng each RT-5: 5¶-GGCCCTGACCCTCACCCC-3¶; RT-3: previously (20). Purified genomic DNA was BglII/EcoRV–digested and 5¶-CAGATGTGCCGCCTCCCTCC-3¶, reverse transcription-PCR (RT-PCR)], fragments were resolved in an agarose gel. After the transfer, the membrane h-actin (10 ng), 1 unit Taq polymerase, and 30 amplification cycles. was probed with radioactive cDNAs specific for ZKSCAN3 (ZNF306) or ZKSCAN3 primers were located in exons 6 and 7, respectively, with a PCR BAGE3 (residing at 21p11.2, a region unaltered in colon cancer); the latter product of 294 bp. was used for normalization. Generation of an anti-ZKSCAN3 antibody. Hydrophobicity of the ZKSCAN3 (ZNF306) protein sequence was analyzed by a Kyte-Doolittle Hydropathy Plot. A Blast search indicated that the EGSRERFRGFRYPE Results was unique and this keyhole limpet hemocyanin–conjugated peptide A ZKSCAN3 overexpression in colorectal cancer. In querying (200 g) was injected
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