Expression profiling identified IL-8 as a regulator of homotypic cell-in-cell formation

Abstract

Homotypic cell-in-cell (CIC) structures forming between cancer cells were proposed to promote tumor evolution via entosis, a nonapoptotic cell death process. However, the mechanisms underlying their formation remained poorly understood. We performed a microarray analysis to identify genes associated with homotypic CIC formation. Cancer cells differing in their ability to form homotypic CIC structures were selected for the study. Association analysis identified 73 probe sets for 62 candidate genes potentially involved in CIC formation. Among them, twenty-one genes were downregulated while 41 genes were upregulated. Pathway analysis identified a gene interaction network centered on IL-8, which was upregulated in high CIC cells. Remarkably, CIC formation was significantly inhibited by IL-8 knockdown and enhanced upon recombinant IL-8 treatment, which correlated with altered cell-cell adhesion and expression of adhesive molecules such as P-cadherin and γ-catenin. Together, our work identified IL-8 as a positive regulator of homotypic CIC formation via enhancing intercellular adhesion.

Biological relevance of cell-in-cell in cancers

“…These data suggest that entosis represents a safety mechanism to remove ‘abnormal’, detached cells from a tissue. Other activators of entosis include reactive oxygen species, methylselenoesters, epidermal growth factor, IL-8 and serum [8–13] (Figure 1A), some of which might trigger entosis simply by causing mitosis or apoptosis.…”

“…A prerequisite for entosis is an interaction between the two cells, which is mediated through the catenin and cadherin adhesion molecules [3,13,14]. To form a CIC structure, the driver cell needs to be relatively rigid, whereas the external cell requires high deformability to extend its membrane all the way around the invading cell [15].…”

“…Perhaps entosis could provide a safe environment in which a tumour cell might avoid both chemotoxic drug exposure and immune surveillance similar to oligodendrocytes sheltering in astrocytes upon inflammation and tissue damage [27]. The fact that certain chemotherapeutic drugs, including taxols [6] as well the pro-inflammatory signal IL-8 can promote CIC formation would favour this idea [13]. However, the invading driver cell does risk being killed and further evidence that tumour cells actively invade into other cells upon drug exposure is needed.…”

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).…”

Counteracting Genome Instability by p53-dependent Mintosis

“…Introduction 49 Cell division via mitosis is strictly regulated to ensure the production of healthy daughter 50 cells. During mitosis, correct segregation and distribution of genetic materials into daughter cells 51 rely on proper activation of spindle assemble checkpoint (SAC) (Musacchio, 2015;Sivakumar & Multiple factors, including CDKN2A (Liang et al, 2018), IL-8 (Ruan et al, 2018a) and membrane 73 cholesterol and lipids (Ruan et al, 2018b), that affects RhoA signaling were recently identified as 74 important regulators of entotic CIC formation. Although initially viable, majority of the internalized 75 cells die non-autonomously with the assistance of outer host cells (Florey et al, 2011).…”