PFN2, a novel marker of unfavorable prognosis, is a potential therapeutic target involved in esophageal squamous cell carcinoma

Abstract

BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most aggressively malignant tumors with dismal prognosis. Profilin 2 (PFN2) is an actin-binding protein that regulates the dynamics of actin polymerization and plays a key role in cell motility. Recently, PFN2 have emerged as significant regulators of cancer processes. However, the clinical significance and biological function of PFN2 in ESCC remain unclear.MethodsPFN2 protein expression was validated by immunohistochemistry (IHC) on tissue microarray from Chinese Han and Kazakh populations with ESCC. The associations among PFN2 expression, clinicopathological features, and prognosis of ESCC were analyzed. The effects on cell proliferation, invasion and migration were examined using MTT and Transwell assays. Markers of epithelial–mesenchymal transition (EMT) were detected by Western blot analysis.ResultsCompared with normal esophageal epithelium (NEE), PFN2 protein expression was markedly increased in low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and ESCC, increased gradually from LGIN to ESCC, and finally reached high grade in HGIN in the Han population. Similarly, PFN2 protein was more overexpressed in ESCC than in NEE in the Kazakh population. The results of Western blot analysis also showed that PFN2 expression was significantly higher in the ESCC tissue than in a matched adjacent non-cancerous tissue. PFN2 expression was positively correlated with invasion depth and lymph node metastasis. High PFN2 expression was significantly correlated with short overall survival (OS) (P = 0.023). Cox regression analysis revealed that PFN2 expression was an independent prognostic factor for poor OS in ESCC. Downregulation of PFN2 inhibited, rather than proliferated, cell invasion and migration, as well as induced an EMT phenotype, including increased expression of epithelial marker E-cadherin, decreased mesenchymal marker Vimentin, Snail, Slug and ZEB1, and morphological changes in ESCC cells in vitro.ConclusionsOur findings demonstrate that PFN2 has a novel role in promoting ESCC progression and metastasis and portending a poor prognosis, indicating that PFN2 could act as an early biomarker of high-risk population. Targeting PFN2 may offer a promising therapeutic strategy for ESCC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0884-y) contains supplementary material, which is available to authorized users.

Tissue protein biomarker candidates to predict progression of esophageal squamous cell carcinoma and precancerous lesions

“…CTGF protein expression was notably correlated to poor survival of ESCC patients after 12 years of follow‐up . An atypical expression pattern of SLC39A6 and PFN2 was observed between different lesion stages, showing that high expression of SLC39A6 and PFN2 was associated with shorter overall survival . Low expression of certain proteins has also been associated with poor prognosis.…”

“…These studies suggest that deregulated proteins with no obvious linear patterns (i.e., not trending up or down) could be potential biomarkers, and that focusing on distinct precancerous lesions rather than invasive carcinoma may help uncover new potential protein biomarkers for early detection. Another study reported an atypical expression pattern of SLC39A6 and profilin 2 (PFN2) at different stages; SLC39A6 and PFN2 expression increased in succession from normal to LGIN, to ESCC, and, finally, reached their peak in HGIN lesions, suggesting the potential diagnostic role of SLC39A6 and PFN2 in ESCC …”

“…Another study reported an atypical expression pattern of SLC39A6 and profilin 2 (PFN2) at different stages; SLC39A6 and PFN2 expression increased in succession from normal to LGIN, to ESCC, and, finally, reached their peak in HGIN lesions, suggesting the potential diagnostic role of SLC39A6 and PFN2 in ESCC. 38,39 Expression pattern and position of biomarker. Other studies have focused not only on the expression level, but on the expression pattern and position of protein biomarker candidates ( Table 2).…”

“…32 An atypical expression pattern of SLC39A6 and PFN2 was observed between different lesion stages, showing that high expression of SLC39A6 and PFN2 was associated with shorter overall survival. 38,39 Low expression of certain proteins has also been associated with poor prognosis. For instance, low TUSC3 expression has been statistically significantly associated with shorter overall survival.…”

PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease

“…It must be pointed out that we detected PFN2 expression as a whole and did not distinguish its two isoforms. PFN2 has been recently described as a potential diagnostic biomarker and therapeutic target for oesophageal squamous cell carcinoma 22. Intriguingly, an increase in PFN2 expression has been described in an intermediate spinal muscular atrophy (SMA) mouse model of axonal degeneration suggesting affected actin dynamics 23…”