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

Abstract

This study aimed to investigate the inactivation of the parkin gene by promoter methylation and its relationship with genome instability in nasopharyngeal carcinoma. Parkin was considered as a tumor suppressor gene in various types of cancers. However, its role in nasopharyngeal carcinoma is unexplored. Genomic instabilities were detected in nasopharyngeal carcinoma tissues by the random amplified polymorphic DNA. The methylation-specific polymerase chain reaction, semi-quantitative reverse transcription polymerase chain reaction, and immunohistochemical analysis were used to detect methylation and mRNA and protein expression of parkin in 54 cases of nasopharyngeal carcinoma tissues and 16 cases of normal nasopharyngeal epithelia tissues, and in 5 nasopharyngeal carcinoma cell lines (CNE1, CNE2, TWO3, C666, and HONE1) and 1 normal nasopharyngeal epithelia cell line (NP69). mRNA expression of parkin in CNE1 and CNE2 was analyzed before and after methyltransferase inhibitor 5-aza-2-deoxycytidine treatment. The relationship between promoter methylation and mRNA expression, demethylation and mRNA expression, and mRNA and protein expression of the gene and clinical factors and genomic instabilities were analyzed. The mRNA and protein expression levels were significantly reduced in 54 cases of human nasopharyngeal carcinoma compared with 16 cases of normal nasopharyngeal epithelia. Parkin-methylated cases showed significantly lower mRNA and protein expression levels compared with unmethylated cases. After 5-aza-2-deoxycytidine treatment, parkin mRNA expression was restored in CNE1 and CNE2; 92.59% (50/54) of nasopharyngeal carcinoma demonstrated genomic instability. Parkin is frequently inactivated by promoter methylation, and its mRNA and protein expression correlate with lymph node metastasis and genomic instability. Parkin deficiency probably promotes tumorigenesis in nasopharyngeal carcinoma.

Overexpression of Parkin in clear cell renal cell carcinoma decreases tumor aggressiveness by regulating CKS2 levels

“…It was demonstrated that cells overexpressing PARK2 had a lower migratory and invasive capacity in vitro . This tumor suppressive phenotype linked to PARK2 expression has been observed previously in different cancer types, including non-small cell lung cancer ( 39 ), breast cancer ( 10 ) and nasopharyngeal carcinoma ( 31 ). Notably, PARK2 deficiency in melanoma cells suppressed migration by inhibiting mitofusin 2 (MFN2) ubiquitination; however, contradictorily, malignant melanoma and metastatic malignant melanoma tissue analyses revealed higher levels of PARK2 and MFN2 ( 40 ).…”

Parkin gene mutations are not common, but its epigenetic inactivation is a frequent event and predicts poor survival in advanced breast cancer patients

“…Addressing the molecular cause for Parkin loss, next we focused on its promoter methylation. It is reported that the Parkin promoter sequence contains distinct CpG islands that are frequently methylated in other cancers [15, 22]. As far as the authors are aware, we provide the first evidence that promoter methylation is a major event for the Parkin inactivation in breast cancer.…”

“…It is an emerging molecular marker which raises the hopes for the development of novel therapeutics in combating cancer [20, 21]. Recent studies have reported aberrant methylation at Parkin promoter among acute lymphoid leukemia (ALL), chronic granulocytic leukemia (CGL) [15], nasopharyngeal carcinoma [22] and cervical cancer [9]. Although the precise genetic and epigenetic mechanisms contributing to Parkin loss in breast cancer remain elusive, this prompted us to investigate the possible mechanisms as well as the potential role of Parkin gene in breast cancer.…”

Parkinson's disease‐associated protein Parkin: an unusual player in cancer

“…Metastasis is a major cause of cancer-related death. Parkin expression is significantly lower in tumors with lymph node metastases than in tumors without such metastases in the case of clear-cell renal cell carcinoma [ 56 ], pancreatic cancer and nasopharyngeal carcinoma [ 47 , 57 ]. Work from our laboratory has shown that Parkin is frequently down-regulated in breast cancer, and that lower Parkin expression correlates with worse distant metastasis-free survival [ 24 ].…”