PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice

Abstract

In 100 primary colorectal carcinomas, we demonstrate by array comparative genomic hybridization (aCGH) that 33% show DNA copy number (DCN) loss involving PARK2, the gene encoding PARKIN, the E3 ubiquitin ligase whose deficiency is responsible for a form of autosomal recessive juvenile parkinsonism. PARK2 is located on chromosome 6 (at 6q25-27), a chromosome with one of the lowest overall frequencies of DNA copy number alterations recorded in colorectal cancers. The PARK2 deletions are mostly focal (31% ∼0.5 Mb on average), heterozygous, and show maximum incidence in exons 3 and 4. As PARK2 lies within FRA6E, a large common fragile site, it has been argued that the observed DCN losses in PARK2 in cancer may represent merely the result of enforced replication of locally vulnerable DNA. However, we show that deficiency in expression of PARK2 is significantly associated with adenomatous polyposis coli (APC) deficiency in human colorectal cancer. Evidence of some PARK2 mutations and promoter hypermethylation is described. PARK2 overexpression inhibits cell proliferation in vitro. Moreover, interbreeding of Park2 heterozygous knockout mice with Apc Min mice resulted in a dramatic acceleration of intestinal adenoma development and increased polyp multiplicity. We conclude that PARK2 is a tumor suppressor gene whose haploinsufficiency cooperates with mutant APC in colorectal carcinogenesis.array | comparative genomic hybridization | mouse model | PARKIN

Elevated TRAF2/6 expression in Parkinson's disease is caused by the loss of Parkin E3 ligase activity

“…However, deletion of Parkin has also been reported in human cancer tissues. 13,14 These findings are inconsistent with our first premise. To resolve these conflicting data, we proposed the hypothesis that Parkin would be linked to inflammation, which can promote cell death and can also induce cancer.…”

“…This function explains frequent Parkin mutations found in human cancers. 13,14 Because cancer cells originate from replaceable epithelial cells, chronic inflammation can trigger cell proliferation, which will contribute to the progression of the cancer. Thus, Parkindeficient cells will be more sensitive to inflammation.…”

“…Recently, based on the frequent deletion or mutation in human colon cancer, Parkin has been suggested as a haploinsufficient tumor suppressor gene. 13,14 As chronic inflammation is tightly related with colon cancer as well as PD, 15,16 we examined the biological role of Parkin in the cytokine-induced inflammation response.…”

Inactivation of parkin by promoter methylation correlated with lymph node metastasis and genomic instability in nasopharyngeal carcinoma

“…4 However, parkin gene deletion and inactivation has been identified frequently in human malignant tumors such as colorectal cancer, lung cancer, leukemia, ovarian cancer, cervical carcinoma, pancreatic cancer, glioma, and so forth. [5][6][7][8][9][10][11][12] Furthermore, parkin deletion in Apc mutant mice accelerated intestinal adenoma development and increased polyp multiplicity. 5 Parkin deficiency sensitizes mice to γ-irradiation-induced tumorigenesis.…”

“…[5][6][7][8][9][10][11][12] Furthermore, parkin deletion in Apc mutant mice accelerated intestinal adenoma development and increased polyp multiplicity. 5 Parkin deficiency sensitizes mice to γ-irradiation-induced tumorigenesis. 13 Knockdown of parkin expression promotes the proliferation and tumorigenic properties of pancreatic cancer cells both in vitro and in mice.…”