Piccolo mediates EGFR signaling and acts as a prognostic biomarker in esophageal squamous cell carcinoma

Abstract

The presynaptic cytomatrix protein Piccolo, encoded by PCLO, is frequently mutated and amplified in esophageal squamous cell carcinoma (ESCC), but its exact roles in ESCC remain unclear. Here we report that Piccolo expression correlates significantly with clinical stage, patient survival and tumor embolus. Functional studies demonstrate that PCLO knockdown remarkably attenuates ESCC malignancy in vitro and in vivo, and ectopic EGFR expression partially compensates for Piccolo loss. PCLO knockdown promotes ubiquitination and degradation of EGFR, which is associated with the negative regulatory effect of Piccolo on E3 ligase Siah1. An anti-Piccolo monoclonal antibody inhibited tumor proliferation in a mouse model of ESCC. These results demonstrate that Piccolo contributes to tumor aggressiveness in ESCC, likely by stabilizing EGFR and promoting EGFR-dependent signaling. Our results further suggest that Piccolo may represent a novel prognostic biomarker and therapeutic target for patients with ESCC.

Gene expression profiling reveals the plausible mechanisms underlying the antitumor and antimetastasis effects of Andrographis paniculata in esophageal cancer

“…EGFR is involved in cell proliferation, migration, invasion, and angiogenesis through different signal transduction pathways. The proportion of EC patients with EGFR overexpression ranges from 36.6% to 97%, and such overexpression is associated with lymph node metastasis, survival rate, and pathologic tumor stages (Zhang et al, ). The present data showed the reduced EGFR gene expression in APW‐treated cells as well as the decreased level of HER2 gene and protein after APW exposure as demonstrated in our previous study (Li et al, ), suggesting that ErbB signaling pathway is also contributed to the inhibitory effects of APW.…”

Cancer/testis antigen‐Plac1 promotes invasion and metastasis of breast cancer through Furin/NICD/PTEN signaling pathway

“…The UltraVision Quanto Detection System (Thermo Fisher Scientific, Waltham, MA, USA) was used, and signals were visualized with DAB Quanto Chromogen provided in the same kit. The intensity of immunostaining was determined by combining the proportion of positively stained tumor cells and the intensity of staining (Zhang et al ., ). Scores representing positive tumor cell proportions were graded as 0, < 5%; 1, 5–25%; 2, 26–50%; 3, 51–75%; and 4, > 75%.…”

The role of Piccolo in cancer treatment: relationship with EGFR and related therapies, and a marker for new targeted therapies

“…Overall, Piccolo acts via the EGFR pathway to modulate malignancy, in terms of cell growth, colony formation, migration and invasion (2). Moreover they found that ESCC patients with high expression of both Piccolo and EGFR levels had a worse prognosis than patients with high expression of only one of them (3).…”

“…The role of Piccolo in cancer treatment: relationship with EGFR and related therapies, and a marker for new targeted therapies the authors observed a significant association of Piccolo overexpression (at protein level) with the risk of lymph node metastasis, a higher clinical stage, poor overall survival (OS) and poor disease free survival (DFS) (3,8).…”

“…One of the new markers identified by Song and colleagues is the PCLO gene, which encodes for a large multi-domain protein, named Piccolo. In the last study of Song and colleagues' group ("Piccolo mediates EGFR signaling and acts as a prognostic biomarker in esophageal squamous cell carcinoma" by Zhang W, Hong R, Xue L, et al, recently published on Oncogene), this protein was extensively characterized, also in terms of interactions with other proteins (1,3).…”