Down‐regulation of insulin‐like growth factor binding protein‐5 (IGFBP‐5): Novel marker for cervical carcinogenesis

Abstract

To better understand the underlying pathways of cervical carcinogenesis, cDNA microarray analysis was performed on 2 sets of squamous cell carcinomas (SCCs) and their adjacent normal squamous epitheliums. Consistently altered expression was detected for 32 genes. Real-time RT-PCR analysis was conducted on a selected subset of these genes (S100A2, GPC4, p72, IGFBP-5, TRIM2 and NAB2) for 14 additional SCCs and 10 normal epithelia. This found that, of the 6 candidate genes, only the insulin-like growth factor binding protein-5 (IGFBP-5) mRNA was generally and significantly under-expressed in SCCs (p < 0.001). All normal cervical epithelia (30 of 30) stained positively for IGFBP-5 protein, with 70% showing strong staining, whereas 65% (17/26) of SCC had complete loss of IGFBP-5, and only 8% (2/26) SCC retained strong expression (p < 0.001). Immunohistochemistry of premalignant cervical intraepithelial neoplasia (CIN) lesions shows a significantly weaker or negative staining in advanced CIN3 lesions compared with normal squamous epithelia (p 5 0.001). This is the first study to show that down-regulation of IGFBP-5 protein correlates with cervical carcinogenesis and does so at a preneoplastic stage. ' 2007 Wiley-Liss, Inc.Key words: squamous cell carcinoma (SCC); cervical intraepithelial neoplasia (CIN); human papillomavirus (HPV); insulin-like growth factor binding protein-5 (IGFBP-5); cDNA microarray; real-time RT-PCR; immunohistochemistry Uterine cervical cancer is the second most common malignancy among women worldwide, 1 with an estimated 470,000 new cases per year 2 and mortality rate which ranks third worldwide, with the highest rates occurring in developing countries.3 Squamous cell carcinomas account for the majority of cervical cancers, followed by adenocarcinomas which comprise 10-18% of cases, and the remainder of tumors consists of a few rare types. 4,5 The squamous cell carcinomas and adenocarcinomas are mainly caused by infection with one of the high-risk types of human papillomaviruses (HPV), exemplified by the HPV-16 and -18 strains; so called highrisk because of their consistent detection in high-grade squamous intraepithelial cervical lesions and carcinomas.6,7 The E6 and E7 viral oncoproteins of high-risk HPV play critical roles in initiating cervical carcinogenesis by binding to and degrading or inactivating the cellular tumor suppressor proteins p53 and Rb.8-13 These viral-oncogenic properties have provided the general basis for the extensive investigations of the role of HPV in carcinogenesis of the HPV-infected cervix, demonstrating how they subvert key cell cycle and regulatory processes to transform and immortalize the host cell. 14,15 It follows that alterations of protein and mRNA expressions in cervical cancer have been investigated specific to the HPV infection; however, the more global profile of gene expression variation between cervical cancer and normal squamous epithelium is still largely unknown. The exploration of cancer-specific up-and down-regulation of genes based on expression ...

The C-terminus of IGFBP-5 suppresses tumor growth by inhibiting angiogenesis

“…Reports on the expression and function of IGFBP-5 in various cancers have been contradictory581332, and in this study we found that IGFBP5 was significantly downregulated in ovarian cancer patient tissues and ovarian cancer cell lines relative to normal controls. Ectopic expression of IGFBP-5 induced cell death in ovarian cancer cells, demonstrating its function as a tumor suppressor.…”

“…IGFBP-5 was initially demonstrated to inhibit IGF function in cell growth, survival, and differentiation by blocking the interaction between IGF and the IGF receptor6; however, an IGF-independent function of IGFBP-5 has subsequently been reported7. The expression level of IGFBP-5 in solid tumors differs depending on cancer type5891011 and in some cancers the expression level of IGFBP-5 has been suggested as a prognostic marker121314.…”

Identification of a Novel Bcl-2-interacting Mediator of Cell Death (Bim) E3 Ligase, Tripartite Motif-containing Protein 2 (TRIM2), and Its Role in Rapid Ischemic Tolerance-induced Neuroprotection

“…It was shown that TRIM2 was associated with microtubule associated motor protein myosin V (20). TRIM2 was also identified in a cancer genomic paper as being down-regulated in cervical squamous cell carcinoma using gene chip microarrays, although further analysis with real time RT-PCR shows that TRIM2 changes were not consistent (22).…”

Screening and analysis of pathogenic genes during DMBA-induced buccal mucosa carcinogenesis in golden hamsters

“…Previous studies (20)(21)(22)(23)(24)(25)(26)(27)(28)(29) indicated that 9 of the 15 genes were associated with the occurrence and development of tumors or were abnormally expressed in tumor tissues. The up-regulation of the Pthlh gene was reported to promote cell proliferation (20).…”

“…Krt10 is a marker of epithelial differentiation and its expression gradually decreased during malignant transformation of normal epithelial cells (27). Miyatake et al reported (28) that the expression of Trim2 was down-regulated in squamous cell carcinoma. Our results indicated that the expression pattern of the 8 genes above was the same as that reported by the previous studies.…”