University of Groningen on the Elucidation of a Tumour Suppressor

University of Groningen On the elucidation of a tumour suppressor role of 3p in lung cancer Elst, Arja ter IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2006 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Elst, A. T. (2006). On the elucidation of a tumour suppressor role of 3p in lung cancer. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 27-09-2021 Chapter 1 Candidate lung tumour suppressor regions at the short arm of chromosome 3. What evidence is there? Arja ter Elst Charles H.C.M. Buys Department of Medical Genetics, University Medical Center Groningen, Groningen, The Netherlands LUNG CANCER AND THE SHORT ARM OF CHROMOSOME 3 Lung cancer is the leading cause of cancer death among both men and women in the western world. Consistent chromosomal aberrations occurring in lung tumours may provide a clue to the somatic genetic events leading to tumour development. Deletions of the short arm of chromosome 3 are a most common abnormality in lung cancer. They have been reported to occur in approximately 75% of non small cell lung cancer (NSCLC) tumours and in up to 100% of small cell lung cancer (SCLC) tumours (reviewed in Kok et al., 1997; Zabarovsky et al., 2002). Such deletions have also been found in the histological normal tissue surrounding tumours and in preneoplastic and preinvasive lesions (reveiwed in Kok et al., 1997). In addition, 3p deletions have been found in histologically normal tissue of about 50% of smokers and former smokers, not in control individuals (Wistuba et al., 1997). This suggests that losses at the short arm of chromosome 3 represent an early chromosomal change in the development of lung tumours. Moreover, introduction by microcell- mediated chromosome transfer of a normal human chromosome 3 into a lung adenocarcinoma cell line, A549, resulted in a suppression of growth of the transfected cell line in nude mice compared to the growth of the parental cell line (Satoh et al., 1993). The region of interest could be confined by the discovery of overlapping homozygous deletions in three different SCLC cell lines, NCI-H740, GLC20 and NCI-H1450, with a smallest overlap of 370 kb (Daly et al., 1993; Kok et al., 1994; Roche et al., 1996). When a cosmid contig was constructed for the 370 kb smallest region of overlap, a search for genes by cDNA library screening and CpG island identification revealed that the region was gene-rich (Wei et al., 1996). Sequencing of the whole region led by experimental and informatics methods to the identification of 19 genes (Lerman and Minna, 2000). These genes will be discussed later in this chapter. Chapter 1 LOSS OF SEGMENTS OF THE SHORT ARM OF CHROMOSOME 3 IN A VARIETY OF TUMOUR TYPES Hemizygous and homozygous deletions of the short arm of chromosome 3 are also found in a multitude of other epithelial cancers, including renal cell carcinoma, head and neck carcinoma, nasopharyngeal carcinoma, malignant mesothelioma, and uterine cervix carcinoma (Kok et al., 1997). For lung cancer, three non-overlapping deletion regions were described 3p25, 3p21.3 and 3p12-p14 (Hibi et al., 1992). The number of distinct regions on the short arm of chromosome 3 that have been implicated in the development of tumours, has been expanded to seven in recent years. These include the regions indicated in the following as 3p22 AP20, 3p21.3 CER1 and CER2, 3p21 D3F15S2 region, 3p21.3 LUCA, 3p14 FHIT and 3p12 ROBO1 (Fig. 1). The 3p22 AP20 region In small cell lung cancer (SCLC) homozygous deletions at the AP20 region have been reported to occur in the large majority of cases (Senchenko et al., 2004). The smallest region of overlap of homozygous deletions in this region was found in a breast cancer cell line and in a renal cancer cell line (RCC) and mapped between the markers D3S3623 and D3S1298 (Fig.1). This region contains four genes: APRG1, coding for AP20 region protein; ITGA9, coding for integrin alpha 9; CTDSPL, encoding CTD (carboxy-terminal domain, RNA polymerase II, polypeptide A) small phosphatase-like and VILL, coding for villin-like. Altered expression of CTDSPL was detected in a panel of epithelial cancer biopsies and cell lines (Kashuba et al., 2004). In addition, clones from a CTDSPL-transfected RCC cell line and a CTDSPL- transfected SCLC cell line showed an inhibition of tumour growth in nude mice in comparison to the growth of the non-transfected parental cell lines (Kashuba et al., 2004). The 3p21.3 CER1 and CER2 regions SCID tumours caused by cell lines carrying a human chromosome 3 on a mouse fibrosarcoma background show non-random elimination of 3p21.3 sequences that are supposed to contain tumour suppressor genes (Kholodnyuk et al., 1997). Szeles et al. (1997) defined the genetic length of the eliminated region designated CER1, common elimination region 1, as 1.6 cM flanked by D3S1029 and D3S643. The 8 Introduction Figure 1. A map of the short arm of chromosome 3 giving the position of the genes and markers located in the region corresponding with the deletion. physical size of CER1 was further restricted to approx. 1 Mb after the region was covered with a PAC contig (Yang et al., 1999). Seventeen genes are located in CER1 (Fig. 1), whose telomeric border is at D3S3582, while its centromeric border is in the first intron of LRRC2 (Kiss et al., 2002). One of these 17 genes, LTF, coding for lactoferrin, was tested for tumourigenicity by injecting SCID mice with clones from a mouse fibrosarcoma cell line transfected with a PAC containing the gene. The LTF 9 Chapter 1 promoter sequences appeared to become hypermethylated and expression of LTF was lost in derived tumours (Yang et al., 2003). Expression of LTF was also found absent in 18 of 37 SCLC cell lines, 11 of 43 NSCLC cell lines and 7 of 13 primary NSCLC tumours (Iijima et al., 2005). When a human nonpapillary renal cell carcinoma cell line was used as recipient of the human chromosome 3, CER1 appeared to become also eliminated on a human background. The elimination region is flanked by D3S3582 and CCR5, i.e. about 250 kb shorter than CER1 on a mouse background (Kholodnyuk et al., 2002). In addition, a second common elimination region was found, CER2, located between marker RH94338 and marker SHGC154057. In CER2 (Fig.1), seven genes have been identified, including two genes coding for chemokine receptors (Kholodnyuk et al., 2002). It may be noted that in CER1 seven of the 17 genes are encoding chemokine receptors. The 3p21.3 D3F15S2 region UBE1L coding for ubiquitin-activating enzyme E1-like, was isolated from a region considered by Kok et al. (1987) as most consistently reduced to hemizygosity in SCLC, the D3F15S2 locus. The gene was picked up by hybridisation of a lung cDNA library with DNA from a human 3p21 fragment in a Chinese hamster-human hybrid (Carritt et al., 1992). UBE1L spans about 8.5 of genomic DNA. It has 26 exons and an open reading frame of 1009 nucleotides. The gene encodes a member of the E1 ubiquitin-activating enzyme family, which are involved in the modification of proteins with ubiquitin in order to target abnormal or short-lived proteins for degradation. The mRNA concentration of UBE1L in SCLC cell lines was found to be 0.5%-3% of that in normal lung tissue. No mutations or rearrangements of the remaining allele were, however, found in SCLC (Kok et al., 1993). UBE1L expression was found to be enhanced after treatment of an acute promyelocytic leukemia cell line with all-trans- retinoic acid (RA), which induces remission in acute promyelocytic leukemia. UBE1L might mediate degradation of the oncogenic PML/RA receptor of the t(15:17) rearrangement found in acute promyelocytic leukemia (Kitareewan et al., 2002). Treatment of immortalised human bronchial cells with RA also resulted in a higher expression of UBE1L and cotransfection of UBE1L with CCND1 in these cells resulted in a repression of CCND1 in a UBE1L dosage dependent manner (Pitha- Rowe et al., 2004). Since overexpression of Cyclin D1 is frequently observed in tumours and may contribute to tumourigenesis, this is an interesting observation. 10 Introduction The 3p21.3 LUCA region As already discussed this region contains 19 genes (Fig.1). Further homozygous deletions of 3p21.3 were found by FISH in three uncultured lung squamous cell carcinoma tumours, at marker D3S2968 (Todd et al., 1997) and by real-time PCR in four uncultured RCC tumours and four uncultured breast cancer tumours at marker D3S3874 (Senchenko et al., 2004). A mouse fibrosarcoma cell line, A9, containing 2 Mb of the human chromosome 3 which included the 370-kb critical region, showed reduction of tumour growth in a tumourigenicity test (Killary et al., 1992).

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