Abstract
Neural invasion (NI) is an important oncological feature of pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism of NI in PDAC remains unclear. In this study, we found that MUC4 was overexpressed in PDAC tissues and high expression of MUC4 indicated a higher NI incidence than low expression. In vitro, MUC4 knockdown inhibited the migration and invasion of PDAC cells and impaired the migration of PDAC cells along nerve in dorsal root ganglia (DRG)-PDAC cell co-culture assay. In vivo, MUC4 knockdown suppressed the NI of PDAC cells in a murine NI model. Mechanistically, our data revealed that MUC4 silencing resulted in decreased netrin-1 expression and re-expression of netrin-1 in MUC4-silenced cells rescued the capability of NI. Furthermore, we identified that decreased netrin-1 expression was owed to the downregulation of HER2/AKT/NF-κB pathway in MUC4-silenced cells. Additionally, MUC4 knockdown also resulted in the downregulation of pFAK, pSrc, pJNK and MMP9. Taken together, our findings revealed a novel role of MUC4 in potentiating NI via netrin-1 through the HER2/AKT/NF-κB pathway in PDAC.
Highlights
Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths worldwide [1]
Our data showed that MUC4 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) tissues and that its expression correlates with Neural invasion (NI)
NI is a special pattern of invasion and a characteristic pathological feature of PDAC, which correlates with the progression and prognosis in PDAC [23]
Summary
Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths worldwide [1]. The median survival of PC patients is approximately 4.1 months, with a 5-year survival rate lower than 5% [2]. The recurrence rate is as high as 93.6% on account of metastasis [4]. It is important to identify novel therapeutic targets for better treatment of PC. Neural invasion (NI) is extremely common in PDAC and is observed in approximately 71% to 98% of PC specimens [5, 6]. Previous studies have shown that NI is an important prognostic factor for PDAC [7]. NI is strongly associated with local recurrence after curative tumor resection and is a major cause of neuropathic pain [8]. Few studies have investigated the molecular mechanisms underlying NI in PDAC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
