SEL1L Affects Human Pancreatic Cancer Cell Cycle and Invasiveness through Modulation of PTEN and Genes Related to Cell-Matrix Interactions

Abstract

Previously, it was reported that SEL1L is able to decrease the aggressive behavior of human pancreatic tumor cells both in vitro and in vivo. To gain insights into the involvement of SEL1L in tumor invasion, we performed gene expression analysis on the pancreatic cancer cell line Suit-2 subjected to two complementary strategies: upregulation and downregulation of SEL1L expression by stable transfection of the entire cDNA under an inducible promoter and by RNA-mediated interference. SuperArray and real-time analysis revealed that SEL1L modulates the expression of the matrix metalloproteinase inhibitors TIMP1 (P < .04-.03) and TIMP2 (P < .03-.05), and the PTEN gene (P < .03-.05). Gene expression modulations correlate with the decrease in invasive ability (P < .05) and in accumulation of SEL1L-expressing cells in G1. Taken together, our data indicate that SEL1L alters the expression of mediators involved in the remodeling of the extracellular matrix by creating a microenvironment that is unfavorable to invasive growth and by affecting cell cycle progression through promotion of G1 accumulation.

SEL1L expression in non–small cell lung cancer

“…Similar results have been observed in normal and carcinomatous prostatic tissues [7]. Furthermore, in vitro evidences suggest that SEL1L may play crucial roles in the regulation of neoplastic invasiveness by altering the expression or synthesis of mediators involved in extracellular matrix remodeling, thus creating a microenvironment unfavorable to invasive growth [8]. The expression pattern of SEL1L in the different cells is unrelated to gene mutations in that extensive mutation scanning of the entire coding and promoter regions using a whole series of DNAs extracted from different tumors has never identified functional or causative base substitutions.…”

Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1

“…With reference to a number of data reporting an anti-invasive effect of TIMP-1 on cancer cell invasion [23,[25][26][27][28][29][30][31], the present work focussed on the causal link of cannabinoid receptor- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 An invasion-associated effect that is mainly determined by the ability of cancer cells to secrete matrix-degrading enzymes or to modulate their activity rather than on cellular motility was substantiated by the finding that reduced Matrigel invasion was not associated with a decrease of transmigration through uncoated Boyden chambers after cannabidiol treatment.…”

“…[24]). Among the four distinct members of the TIMP family, elevated TIMP-1 was shown to mediate the anti-invasive effects of several anticarcinogenic drugs [23,[25][26][27][28][29]. Furthermore, decreased TIMP-1 levels were demonstrated to correlate with high cancer invasiveness [30,31].…”

mSEL-1L (Suppressor/Enhancer Lin12-like) Protein Levels Influence Murine Neural Stem Cell Self-renewal and Lineage Commitment

“…proposed to be an important element in extracellular matrix interactions (60), likely because of its capacity to alter the expression of molecules involved in extracellular matrix and cytoskeletal remodeling (52,61). It is noteworthy that mSEL-1L (regulating Notch signaling), ␤1-integrin (mediating specific cell-matrix interactions), and Bmi1 (controlling stem cell fate) might belong to the same biochemical pathway regulated by the refined action of miR-183; perhaps together they synergically participate in self-renewal maintenance by creating a specific "niche" environment able to control NSC proliferation, adhesion, and migration.…”