Abstract 4950: Defective expression of partition-defective 3 (PAR-3) is associated with adverse prognostic factors in esophageal squamous cell carcinoma

Abstract

Abstract Esophageal cancer is the sixth leading cause of cancer mortality and squamous cell carcinoma is a prevalent histological subtype worldwide. The partition-defective 3 (PAR-3) protein belongs to a partition defective complex that controls polarity, which is mainly composed of PAR-3, PAR-6, and atypical protein kinase C (aPKC). PAR-3 contains one self-oligomerization domain in the N-terminus, three PDZ protein interaction domains and one aPKC-binding domain. Owing to these domains, PAR-3 is able to form a conserved protein complex with PAR-6 and aPKC. In mammalian epithelial cells, PAR complex assembles at tight junctions, and plays a role in controlling apical-basal polarity, asymmetric cell division, and directional cell migration. It is well known that disrupted cell polarity is a feature of epithelial cancers. Therefore, it is believed that PAR proteins may be involved in multiple aspects of oncogenesis and tumor-promoting function. We previously detected a homozygous deletion of PAR-3 gene in esophageal squamous cell carcinoma (ESCC) cell lines by a high-density oligonucleotide microarray approach. (Oncogene 28:2910-2918, 2009). A copy number loss of PAR-3 gene was observed in 15% of primary ESCC tumors. The expression of PAR-3 mRNA was significantly reduced in 70% of ESCC tumors when compared with their nontumorous tissue counterparts. Exogenous expression of PAR-3 gene in ESCC cells lacking this gene (KYSE30 cells) enhanced the recruitment of Zonula occludens 1 (ZO-1), a marker of tight junctions, to sites of cell-cell contact. Conversely, knockdown of PAR-3 gene in ESCC cells expressing this gene disrupted ZO-1 localization at cell-cell borders. Although our previous findings suggested that deletion and reduced expression of PAR-3 gene may be a novel mechanism that drives the progression of ESCC, the clinical relevance of PAR-3 in ESCC tumor progression was not known. In the present study, we aimed to investigate the expression pattern of PAR-3 protein in primary ESCC tumors and to clarify any potential relationship between the PAR-3 expression and clinicopathological parameters. Immunohistochemical analyses showed that PAR-3 protein was expressed at the basal layer of the normal squamous epithelium of the esophagus, esophageal glands proper and the duct of esophageal glands. Both normal esophageal cells and ESCC tumor cells showed granular cytoplasmic staining and particularly strong membranous staining of PAR-3 protein. PAR-3 protein expression was lost in 20 (37%) of 74 primary ESCC tumors. Loss of PAR-3 protein expression was significantly associated with invasion depth (P = 0.0065) and lymph node metastasis (P = 0.03). Our results suggest that loss of PAR-3 protein expression may lead to tumor progression and subsequent lymph node metastasis in ESCC. Citation Format: Tomoko Kitaichi, Koichiroh Yasui, Akira Tomie, Yasuyuki Gen, Osamu Dohi, Yuji Naito, Yoshito Itoh. Defective expression of partition-defective 3 (PAR-3) is associated with adverse prognostic factors in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4950. doi:10.1158/1538-7445.AM2015-4950