CHC1‐L, a candidate gene for prostate carcinogenesis at 13q14.2, is frequently affected by loss of heterozygosity and underexpressed in human prostate cancer

Abstract

Loss of heterozygosity (LOH) at chromosome 13q14 is one of the most recurrent anomalies observed in sporadic prostate tumors. This LOH is believed to unmask recessive mutations that inactivate a tumor-suppressor gene(s) which otherwise regulates normal cell growth and suppresses abnormal cell proliferation. Identification of potential tumorsuppressor genes within the deleted region is a way of indicating putative pathways of prostate cancer development and progression. The main target that disappears or is downregulated as a result of 13q14 loss remains to be identified. Therefore, our first concern was to find a gene located in the 13q14 region whose transcription is reduced. CHC1-L, for chromosome condensation 1-like, is mapped to the smallest common deleted region. CHC1-L expression is significantly reduced in prostate tumors compared to normal prostate tissues (p ‫؍‬ 0.0002). In 21 of 36 (58%) primary prostate tumors studied, CHC1-L expression was reduced at least 2-fold, as measured by real-time quantitative RT-PCR; 18 of the tumors (50%) showed 13q14 LOH for at least 1 of the 5 polymorphic markers that we studied in the region, and 14 (78%) of these were among the tumors underexpressing CHC1-L. CHC1-L is alternatively spliced at its 5 end to produce 2 isoforms, of 551 and 526 aa. Analyses of CHC1-L integrity and of the quantitative expression of its variants indicate that the observed underexpression in prostate tumors is related to reduced expression of the 551 aa isoform. Although CHC1-L is not the obvious candidate given its only known homology, to RCC1, a guanine nucleotide exchange factor for the Ras-related GTPase Ran, the frequent significant decrease observed in its expression in prostate cancer associated with the difference in frequency of CHC1-L variant isoforms between normal and neoplastic prostate tissues places it in a pivotal role or possibly adjacent to a gene that has that role in prostate cancer evolution. © 2002 Wiley-Liss, Inc. Key words: CHC1-L; prostate cancer; loss of heterozygosity; 13q14 locus; real-time quantitative RT-PCRProstate cancer, one of the most common malignancies among men in Western countries, 1 develops and progresses, like other neoplastic diseases, through an accumulation of genetic alterations. The exact molecular mechanisms underlying the onset and progression of prostate cancer are unclear, but the most frequent type of tumor-associated mutation is somatic loss of heterozygosity (LOH) in distinct chromosomal regions. 2 One of the most recurrent aberrations observed in prostate tumors involves chromosome arm 13q, as shown by molecular analyses. [3][4][5] We and others have found a smallest common deleted region on chromosome 13q14 in primary prostate tumors, 6 -10 pointing to a gene with an important role in the initiation and/or progression of prostatic carcinoma. LOH was initially suspected to affect the retinoblastoma susceptibility gene (RB1) located in the commonly deleted region. However, we and others failed to correlate LOH at the RB1 locus with decreased...

MicroRNAs and prostate cancer

“…Few genes have been described as the main targets of losses of heterozygosity, including NKX33-1 at 8p21, PTEN at 10q23.3 and KLF5 at 13q21 (Dong 2001). Despite the presence of two important tumour suppressor genes at 13q, namely BRCA2 and RB1, no correlation between LOH and down-regulation of these genes has been observed (Latil et al 1999(Latil et al , 2002. A detailed analysis of microsatellite markers on 13q identified a minimal region of loss of 800 kb at 13q14.2-q14.3 (Ueda et al 1999, Yin et al 1999, Chen et al 2001.…”

Alteration of gene expression in response to bone morphogenetic protein-2 in androgen-dependent human prostate cancer LNCaP cells

“…Loss of heterozygosity of chromosome 13q14.2-q14.3 is one of the most frequent aberrations observed in prostate tumors (21)(22)(23)(24)(25). CHC1L is located in the last region and differs significantly in expression between normal and neoplastic prostate tissue (26). CHC1L may be important in the control of nuclear-cytoplasmic transport and cell cycle progression through a Ras-related signal transduction pathway.…”

Expression in bladder transitional cell carcinoma by real‐time quantitative reverse transcription polymerase chain reaction array of 65 genes at the tumor suppressor locus 9q34.1‐2: Identification of 5 candidates tumor suppressor genes

“…Total RNA was extracted from tissue specimens and reverse transcribed as previously described by Latil et al 13 …”

“…For each gene, primers were selected as described previously by Latil et al 13 and sequences are available upon request.…”