Dual roles of hemidesmosomal proteins in the pancreatic epithelium: the phosphoinositide 3-kinase decides

Abstract

Given the failure of chemo- and biotherapies to fight advanced pancreatic cancer, one major challenge is to identify critical events that initiate invasion. One priming step in epithelia carcinogenesis is the disruption of epithelial cell anchorage to the basement membrane which can be provided by hemidesmosomes (HDs). However, the existence of HDs in pancreatic ductal epithelium and their role in carcinogenesis remain unexplored. HDs have been explored in normal and cancer pancreatic cells, and patient samples. Unique cancer cell models where HD assembly can be pharmacologically manipulated by somatostatin/sst2 signaling have been then used to investigate the role and molecular mechanisms of dynamic HD during pancreatic carcinogenesis. We surprisingly report the presence of mature type-1 HDs comprising the integrin α6β4 and bullous pemphigoid antigen BP180 in the human pancreatic ductal epithelium. Importantly, HDs are shown to disassemble during pancreatic carcinogenesis. HD breakdown requires phosphoinositide 3-kinase (PI3K)-dependent induction of the matrix-metalloprotease MMP-9, which cleaves BP180. Consequently, integrin α6β4 delocalizes to the cell-leading edges where it paradoxically promotes cell migration and invasion through S100A4 activation. As S100A4 in turn stimulates MMP-9 expression, a vicious cycle maintains BP180 cleavage. Inactivation of this PI3K-MMP-9-S100A4 signaling loop conversely blocks BP180 cleavage, induces HD reassembly and inhibits cell invasion. We conclude that mature type-1 HDs are critical anchoring structures for the pancreatic ductal epithelium whose disruption, upon PI3K activation during carcinogenesis, provokes pancreatic cancer cell migration and invasion.

Complement in bullous pemphigoid: results from a large observational study

“…In an experimental BP180 humanized mouse model, skin fragility was induced by passive transfer of F(ab′) 2 fragments, and in C3‐deficient mice, blister formation could be induced by passive transfer of anti‐BP180 antibodies from patients with BP . Another complement‐independent mechanism of disruption of the hemidesmosome has been described in pancreatic ductal adenocarcinoma, in which cleavage of the extracellular domain of BP180 by MMP‐9 has been shown to be dependent on the phosphoinositide 3‐kinase pathway …”

IL‐1β promotes the nuclear translocaiton of S100A4 protein in gastric cancer cells MGC803 and the cell's stem‐like properties through PI3K pathway

“…The activation of PTEN/PI3K/AKT signaling by hepatitis B X‐interacting protein (HBXIP) subsequently boosted S100A4 expression in breast cancer cells . Inhibiting PI3K in BxPC‐3 pancreatic cancer cells also abrogates S100A4 expression . Inhibition of Akt by Akti, effectively blocks α6β4‐dependent S100A4 expression .…”

Loss of Somatostatin Receptor Subtype 2 Promotes Growth of KRAS-Induced Pancreatic Tumors in Mice by Activating PI3K Signaling and Overexpression of CXCL16

“…These findings are consistent with the concept that altering the endogenous sst2 brake may confer an advantage for Our previous data demonstrated that sst2 expression in pancreatic cancer cells inhibits their tumorigenicity / invasion, with those sst2 tumor suppressive functions relying on PI3K inhibition. [11][12][13] Mechanistically, somatostatin-activated sst2 inhibits PI3K activity by disrupting a pre-existing complex comprising the sst2 receptor and the p85 PI3K regulatory subunit which directly interact.…”

“…10 Importantly, inhibition of phosphoinositide 3-kinase (PI3K) and of nuclear factor-κB (NF-κB) underlies sst2 tumor suppressive activity in pancreatic cancer cells. [11][12][13] Activation of PI3K activity is required for Kras-initiated carcinogenesis and maintenance, and high PI3K activity is observed in nearly all PDAC. [14][15][16] Yet, no mutation has been found in PI3K itself or any regulatory genes which could explain the high activation of PI3K generally observed in PDAC.…”