Distinct regions of allelic imbalance on chromosome 10q22-q26 in squamous cell carcinomas of the lung

Petersen, Simone; Rudolf, Jacqueline; Bockmühl, Ulrike; Gellert, Klaus; Wolf, Günter; Dietel, Manfred; Petersen, Iver

doi:10.1038/sj.onc.1201949

Cited by 46 publications

(40 citation statements)

References 24 publications

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“…It has been reported that alterations in more than one gene within the 10q22-10q26 region may be involved in human cancer development (1). In the present study, mutations in exon 15 of Ikk␣ were detected in human SCCs.…”

Section: Discussionsupporting

confidence: 49%

See 1 more Smart Citation

A critical role for IκB kinase α in the development of human and mouse squamous cell carcinomas

Liu

Park

Zhu

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

116

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IKK (I B kinase) ␣ is essential for embryonic skin development in mice. Mice deficient in IKK␣ display markedly hyperplasic epidermis that lacks terminal differentiation, and they die because of this severely impaired skin. However, the function of IKK␣ in human skin diseases remains largely unknown. To shed light on the role of IKK␣ in human skin diseases, we examined IKK␣ expression and Ikk␣ mutations in human squamous cell carcinomas (SCCs). We found a marked reduction in IKK␣ expression in poorly differentiated human SCCs and identified Ikk␣ mutations in exon 15 of Ikk␣ in eight of nine human SCCs, implying that IKK␣ is involved in development of this human skin cancer. Furthermore, in a chemical carcinogen-induced skin carcinogenesis setting, mice overexpressing human IKK␣ in the epidermis under the control of a truncated loricrin promoter developed significantly fewer SCCs and metastases than did wild-type mice. The IKK␣ transgene altered the skin microenvironment conditions, leading to elevated terminal differentiation in the epidermis, reduced mitogenic activity in the epidermis, and decreased angiogenic activity in the skin stroma. Thus, overexpression of IKK␣ in the epidermis antagonized chemical carcinogen-induced mitogenic and angiogenic activities, repressing tumor progression and metastases.angiogenesis ͉ mitogenesis ͉ skin carcinogenesis ͉ differentiation ͉ tumor progression S quamous cell carcinomas (SCCs) can be very aggressive and metastatic. Previous studies have shown that Pten mutations are found frequently in human SCCs; however, these Pten mutations are not detected in all cases (1, 2). p53 mutations have also been identified in a large proportion of human SCCs (3); however, these p53 mutations can be latent in skin cells for years before the onset of this disease. Clearly, additional pivotal factors in the development of this human skin cancer remain to be identified.The I B kinase (IKK) complex consists of IKK␣, IKK␤, and IKK␥ (4-7), which phosphorylates I B␣ (S32͞S36) and I B␤ (S19͞S23) that are NF-B inhibitors. This phosphorylation event triggers the degradation of I B proteins via a 26S proteasomeubiquitination pathway, leading to NF-B translocation and activation. Previous findings have shown that IKK␣ is essential for embryonic skin development in mice (8-10). Mice lacking IKK␣ exhibit a strikingly hyperplastic epidermis, which lacks terminal differentiation, and they die of severely impaired skin soon after birth. The skin phenotypes of Ikk␣ Ϫ/Ϫ mice have not been observed in knockouts of any other NF-B family members. In contrast, mice overexpressing IKK␣ in the basal epidermis develop normally (11). The ectopic IKK␣ is able to induce terminal differentiation and to repress hyperplasia in the skin of Ikk␣ Ϫ/Ϫ mice, implying that IKK␣ plays a role in maintaining skin homeostasis (11).Although a role of IKK␣ in skin development in mice has been established, we still know little regarding the involvement of IKK␣ in human skin diseases. To shed light on the role of IKK␣ in human skin ...

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Section: Discussionsupporting

confidence: 49%

“…Previous studies have shown that Pten mutations are found frequently in human SCCs; however, these Pten mutations are not detected in all cases (1,2). p53 mutations have also been identified in a large proportion of human SCCs (3); however, these p53 mutations can be latent in skin cells for years before the onset of this disease.…”

Section: Ikk (I B Kinase)mentioning

confidence: 98%

A critical role for IκB kinase α in the development of human and mouse squamous cell carcinomas

Liu

Park

Zhu

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

116

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“…Rashmi et al 33 found results with activating PIK3CA (E545K, E542K) and inactivating PTEN (R233) mutations were identified in human cervical cancer. An analysis of PTEN gene in squamous cell carcinomas from other sites also found that PTEN is not frequently mutated in the lung 34 , cervix 14 , skin 35 , head and neck 36 or esophagus 37 . Although numerous somatic mutations have been localized in the PTEN gene, these only occur in a minority of tumors, which indicates that alternative mechanisms of PTEN inactivation, both genetic and non-genetic, must exist.…”

Section: Discussionmentioning

confidence: 99%

PTEN expression in patients with carcinoma of the cervix and its association with p53, Ki-67 and CD31

Loures¹,

Cândido²,

Vidigal³

et al. 2014

Rev. Bras. Ginecol. Obstet.

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PURPOSE: To investigate protein expression and mutations in phosphatase and tensin homolog (PTEN) in patients with stage IB cervical squamous cell carcinoma (CSCC) and the association with clinical-pathologic features, tumor p53 expression, cell proliferation and angiogenesis. METHODS: Women with stage IB CSCC (n=20 -Study Group) and uterine myoma (n=20 -Control Group), aged 49.1±1.7 years (mean±standard deviation, range 27-78 years), were prospectively evaluated. Patients with cervical cancer were submitted to Piver-Rutledge class III radical hysterectomy and pelvic lymphadenectomy and patients in the Control Group underwent vaginal hysterectomy. Tissue samples from the procedures were stained with hematoxylin and eosin for histological evaluation. Protein expression was detected by immunohistochemistry. Staining for PTEN, p53, Ki-67 and CD31 was evaluated. The intensity of PTEN immunostaining was estimated by computer-assisted image analysis, based on previously reported protocols. Data were analyzed using the Student's t-test to evaluate significant differences between the groups. Level of significance was set at p<0.05. RESULTS: The PTEN expression intensity was lower in the CSCC group than in the Control (benign cervix) samples (150.5±5.2 versus 204.2±2.6; p<0.001). Our study did not identify any mutations after sequencing all nine PTEN exons. PTEN expression was not associated with tumor expression of p53 (p=0.9), CD31 (p=0.8) or Ki-67 (p=0.3) or clinical-pathologic features in patients with invasive carcinoma of the cervix. CONCLUSIONS: Our findings demonstrate that the PTEN protein expression is significantly diminished in CSCC.

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“…Multiple screening studies for genetic alterations in chromosome 10q in various cancers have frequently revealed two common minimally deleted regions in prostate tumors and other cancers (Cairns et al, 1997;Carter et al, 1990;Gray et al, 1995;Ittmann, 1996;Kim et al, 1998;Petersen et al, 1998). Table 1 summarizes the rates of LOH that have been detected with microsatellite markers within this region.…”

Section: Discussionmentioning

confidence: 99%

“…Loss of heterozygosity (LOH) and homozygous deletions at human chromosomal regions 8p21 ± 22 and 10q23 ± 24 are frequently found in prostate adenocarcinomas, as well as other cancer tumors, and suggest that multiple TSGs are present in each of these locations Cairns et al, 1997;Carter et al, 1990;Gray et al, 1995;Ishii et al, 1999;Ittmann, 1996;Kagan et al, 1995;Kim et al, 1998;Li et al, 1997;Petersen et al, 1998;Whang et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

LAPSER1: a novel candidate tumor suppressor gene from 10q24.3

et al. 2001

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Distinct regions of allelic imbalance on chromosome 10q22-q26 in squamous cell carcinomas of the lung

Cited by 46 publications

References 24 publications

A critical role for IκB kinase α in the development of human and mouse squamous cell carcinomas

A critical role for IκB kinase α in the development of human and mouse squamous cell carcinomas

PTEN expression in patients with carcinoma of the cervix and its association with p53, Ki-67 and CD31

LAPSER1: a novel candidate tumor suppressor gene from 10q24.3

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