PMP22 Regulates Self-Renewal and Chemoresistance of Gastric Cancer Cells

Abstract

Cancer stem cells possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the explorer antibody microarray. We identified PMP22, a target gene of the Wnt/β-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation. Infecting gastric cancer cells with lentivirus expressing PMP22 shRNAs reduced proliferation, tumorsphere formation, and chemoresistance to cisplatin and in NOD/SCID mice. When combined with bortezomib, a PMP22 inhibitor, the chemotherapeutic sensitivity to cisplatin treatment was dramatically increased by inducing cell apoptosis in cultured cells and xenograft mouse models. Finally, mRNA expression levels of PMP22 were detected in 38 tumor specimens from patients who received six cycles of perioperative chemotherapy. A strong correlation between PMP22 level and tumor recurrence was revealed, thus showing a pivotal role of PMP22 in the clinical chemoresistance of gastric cancer. Our study is the first to show the role of PMP22 in gastric cancer stemness and chemoresistance and reveals a potential new target for the diagnosis and treatment of recurrent gastric cancer..

Targeting cancer stem cell pathways for cancer therapy

“…159 PMP22, an integral membrane glycoprotein in myelin in the peripheral nervous system, induces the differentiation of gastric CSCs, but its mRNA level declines with activation of the Wnt/β-catenin pathway. 160 Moreover, TRAP1, a component of the HSP90 (heat-shock protein 90) chaperone family, inhibits the differentiation of colorectal carcinoma stem cells by modulating β-catenin ubiquitination and phosphorylation. 161 Lgr5, a member of the G proteincoupled receptor (GPCR) family of proteins, is located downstream of the Wnt signaling pathway and restrains the differentiation of esophageal SCC stem cells.…”

Winding back Wnt signalling: potential therapeutic targets for treating gastric cancers

“…While it is likely that Wnt6 + ‐resistant cells represent gCSCs, this was not formally demonstrated. More recently, investigations to identify cell‐surface proteins that mark chemoresistant and self‐renewing GC cells following chemotherapy (cisplatin) reveal enrichment for the cell‐surface glycoprotein PMP22 (Cai et al , ). PMP22, a Wnt target gene, is expressed in patients that had undergone perioperative chemotherapy, highlighting a strong correlation between PMP22 expression and tumour recurrence.…”

“…PMP22, a Wnt target gene, is expressed in patients that had undergone perioperative chemotherapy, highlighting a strong correlation between PMP22 expression and tumour recurrence. GC cells and tumour xenograft sensitivity to cisplatin were significantly increased when combined with pharmacological inhibition of PMP22 (Cai et al , ). The cell‐surface water channel protein aquaporin‐3 (AQP3) is overexpressed in GC tissues and promotes invasion and metastasis via EMT (Chen et al , ); however, its role in chemoresistance has only recently been investigated.…”

Gastric cancer: Basic aspects

“…These results show that CCAR1 plays a role in gastric carcinogenesis and is a potential biomarker . Furthermore, an upregulation of PMP22, a Wnt/β‐catenin target gene, was found in GC cells resistant to cisplatin by Cai et al., and its inhibition decreased CSC properties both in vitro and in vivo. In this study, the treatment with a PMP22 inhibitor restores the sensibility to cisplatin treatment and PMP22 expression correlated with a worst clinical outcome in patients of GC.…”

“…These results show that CCAR1 plays a role in gastric carcinogenesis and is a potential biomarker. 57 Furthermore, an upregulation of PMP22, a Wnt/β-catenin target gene, was found in GC cells resistant to cisplatin by Cai et al, 58 and its inhibition decreased CSC properties both in vitro and in vivo.…”