PCDH7 Inhibits the Formation of Homotypic Cell-in-Cell Structure

Abstract

Though homotypic cell-in-cell (hoCIC) structures are implicated in the development and progression of multiple human tumors, the molecular mechanisms underlying their formation remain poorly understood. We found that the expression of Protocadherin-7 (PCDH7), an integral membrane protein, was negatively associated with the formation of hoCIC structures. Overexpression of PCDH7 efficiently inhibits, while its depletion significantly enhances, hoCIC formation, which was attributed to its regulation on intercellular adhesion and contractile actomyosin as well. Via directly interacting with and inactivating PP1α, a protein phosphatase that dephosphorylates pMLC2, PCDH7 increases the level of pMLC2 leading to enhanced actomyosin at the intercellular region and compromised hoCIC formation. Remarkably, PCDH7 enhanced anchorageindependent cell growth in a hoCIC-dependent manner. Together, we identified PCDH7 as the first trans-membrane protein that inhibits hoCIC formation to promote tumor growth.

Role of Heterotypic Neutrophil-in-Tumor Structure in the Prognosis of Patients With Buccal Mucosa Squamous Cell Carcinoma

“…Several chemokines, cytokines and angiogenic factors produced by neutrophils may result in inflammatory cell recruitment and activation that crucially impact the tumor microenvironment, which could facilitate tumor cell proliferation, microvascular regeneration and tumor progression (9,14,15). The formation of CIC structure in tumors is a functional result of active intercellular interactions within heterogeneous tumor microenvironments, which is driven by a set of core molecular elements (16,17) that are regulated by multiple factors, such as cholesterol and IL-8 (18)(19)(20)(21).…”

Involvement of the Actin Machinery in Programmed Cell Death

“…Multiple actin machinery proteins such as E- or P-cadherin, multiple essential catenins, junction localized-p190A RhoGAP, RhoA, ROCK I/II, pMLC2, MHC IIA and IIB and actin, constitute these ring-like complexes and are proved to accumulate at high levels (Sun et al, 2014a ). At the cell-cell contact site, the transmembrane protein PCDH7 can positively regulate the actin machinery protein pMLC2 by inactivating protein phosphatase 1α (PP1α), thereby increasing actomyosin contraction (Wang et al, 2020a ). Additionally, the contractile actomyosin ring was further connected with a dome-like structure formed by cortex F-actin and MLC at the rear region of the invading cell (Wang et al, 2020b ).…”

Role and dynamics of vacuolar pH during cell-in-cell mediated death

“…Recently, the vinculinenriched mechanical ring was identified as a novel core element interfacing between adherens junction and actomyosin to coordinate cell internalization 19 . Besides, a group of factors, by acting on the core elements, were identified to regulate CIC formation, such as PCDH7, CDKN2A, MTRF, and LPA and the like [20][21][22][23][24][25] .…”