Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers

Abstract

Gastric and colorectal cancers are among the most common cancers worldwide and cause serious cancer mortality. Both epigenetic and genetic disruptions of tumour suppressor genes (TSGs) are frequently involved in their pathogenesis. Here, we studied the epigenetic and genetic alterations of a novel TSG-PCDH17 and its functions in the pathogenesis of these tumours. We found that PCDH17 was frequently silenced and methylated in almost all gastric and colorectal tumour cell lines as well as in ∼95% of primary tumours, but not in normal gastric and colonic mucosa. Moreover, its deletion was detected in only 18% of gastric and 12% of colorectal cancer tissues, suggesting that epigenetic and genetic inactivation of PCDH17 are both involved in gastric and colorectal tumourigenesis. PCDH17 protein expression was significantly correlated with low tumour stage and less lymph node metastasis of gastric and colorectal cancer patients, indicating its potential as a tumour marker. Restoring PCDH17 expression inhibited tumour cell growth in vitro and in vivo through promoting apoptosis, as evidenced by increased TUNEL staining and caspase-3 activation. Furthermore, PCDH17-induced autophagy, along with increased numbers of autophagic vacuoles and up-regulated autophagic proteins Atg-5, Atg-12 and LC3B II. Thus, PCDH17 acts as a tumour suppressor, exerting its anti-proliferative activity through inducing apoptosis and autophagy, and is frequently silenced in gastric and colorectal cancers. PCDH17 methylation is a tumour-specific event that could serve as an epigenetic biomarker for these tumours.

Protocadherin 17 promoter methylation in tumour tissue from patients with bladder transitional cell carcinoma

“…20,21 Promoter methylation of PCDH17 has been reported in several human cancers, including bladder cancer, but the clinical significance of PCDH17 methylation in patients with bladder cancer remains unclear. 7,13 The human PCDH17 gene is located on chromosome 13q21.2 and functions as a tumour suppressor in human cancers. 7,13 The PCDH17 protein is a member of the cadherin superfamily.…”

“…7,13 The human PCDH17 gene is located on chromosome 13q21.2 and functions as a tumour suppressor in human cancers. 7,13 The PCDH17 protein is a member of the cadherin superfamily. The protocadherins differ from classic cadherins in that their heterophilic interactions with other molecules may be more important for their various physiological functions than simple cell adhesion involving homophilic interactions.…”

“…The methylation status of the PCDH17 gene was examined by methylation-specific PCR as reported previously. 7 Briefly, the primer sequences for the unmethylated PCDH17 reaction were as follows: PCDH17 unmethylated sense (UMS) (sense), 5 0 -AGATTATTGGGTGTTGTAGTTT-3 0 ; and PCDH17 unmethylated antisense (UMAS) (antisense), 5…”

“…PCDH17 methylation is found in several human carcinomas including urological cancers. 7,12,13 In the present study, the promoter methylation status of PCDH17 in bladder cancer tissue was examined and compared with normal tissues. In addition, the correlation between PCDH17 promoter methylation status and clinicopathological parameters was examined, together with patient outcome, in order to elucidate the clinical significance of PCDH17 promoter methylation in patients with bladder cancer.…”

“…6 Epigenetic modifications, particularly DNA methylation, play an important role in the progression of bladder cancer, since DNA methylation often results in the hypermethylation of selected gene promoters and the inactivation of tumour suppressor genes. 7,8 Identification of novel methylated tumour suppressor genes may be used in the diagnosis, prognosis and therapy of bladder cancer.…”