HGF/c-Met pathway facilitates the perineural invasion of pancreatic cancer by activating the mTOR/NGF axis

Abstract

Perineural invasion (PNI) is a pathologic feature of pancreatic cancer and is associated with poor outcomes, metastasis, and recurrence in pancreatic cancer patients. However, the molecular mechanism of PNI remains unclear. The present study aimed to investigate the mechanism that HGF/c-Met pathway facilitates the PNI of pancreatic cancer. In this study, we confirmed that c-Met expression was correlated with PNI in pancreatic cancer tissues. Activating the HGF/c-Met signaling pathway potentiated the expression of nerve growth factor (NGF) to recruit nerves and promote the PNI. Activating the HGF/c-Met signaling pathway also enhanced the migration and invasion ability of cancer cells to facilitate cancer cells invading nerves. Mechanistically, HGF/c-Met signaling pathway can active the mTOR/NGF axis to promote the PNI of pancreatic cancer. Additionally, we found that knocking down c-Met expression inhibited cancer cell migration along the nerve, reduced the damage of the sciatic nerve caused by cancer cells and protected the function of the sciatic nerve in vivo. Taken together, our findings suggest a supportive mechanism of the HGF/c-Met signaling pathway in promoting PNI by activating the mTOR/NGF axis in pancreatic cancer. Blocking the HGF/c-Met signaling pathway may be an effective target for the treatment of PNI.

Histone acetylation insulator SET orchestrates PP2A inhibition and super-enhancer activation

“…Meanwhile, MET expression was also elevated in PDAC ( Figure S7C ) and the increased MET (c-Met) is positively correlated with Pol II S5-p level and SET level ( Figures 6F , 6G , S7D-S7G ), implying that up-regulation of oncogene MET is part of the hyper-transcription program prompted by SET. Moreover, we observed that MET high expression is correlated with short survival time of PDAC patients, indicating that MET over-expression contributed to the malignancy of PDAC ( Figures S7I and S7J ) in accordance with previous reports (Ebert et al, 1994; Kiehne et al, 1997; Lee et al, 2003; Qin et al, 2022; Yan et al, 2018). In conclusion, IHC study in the PDAC consecutive sections ( Figure 6H ) supported the hypothesis that over-expressed SET, supporting CDK9-induced Pol II CTD phosphorylation, prompts the hyper-transcription of growth-essential genes including the oncogene MET ( Figure 6I ).…”

“…Pol II CTD S5-p is a hallmark of Pol II activation and transcription initiation (Chipumuro et al, 2014;Thandapani, 2019) S7J) in accordance with previous reports (Ebert et al, 1994;Kiehne et al, 1997;Lee et al, 2003;Qin et al, 2022;Yan et al, 2018). In conclusion, IHC study in the PDAC consecutive sections (Figure 6H) supported the hypothesis that over-expressed SET, supporting CDK9-induced Pol II CTD phosphorylation, prompts the hyper-transcription of growth-essential genes including the oncogene MET (Figure 6I).…”

Tumor-associated macrophages and Schwann cells promote perineural invasion via paracrine loop in pancreatic ductal adenocarcinoma

“…Perineural invasion consists of cancer cells in nerves or surrounding or pass-through nerves, tumor cells close to the nerve and surrounding at least 33% of the nerve periphery, or tumor cells invading any of the three layers of the neurolemma structure [20]. PNI is a signi cant determinant of the recurrence and prognosis of pancreatic cancer [21][22][23][24][25][26]. Current studies suggest that Schwann cells play a pivotal role in the development of PNI [14,[27][28][29][30].…”

Pancreatic cancer-related pain: mechanism and management

“…HGF/c-Met pathway in pancreatic stellate cells (PSCs) facilitates and activates the mTOR/NGF axis to promote PNI. [22] Besides, hyperglycemia environment in PC elevates the expression of NGF by upregulating HIF-1α. [23] Paracrine NGF secreted by PC cells induces autophagy of Schwann cells in PNI which promotes reciprocal approaching of neuron axons and cancer cells.…”