Partial restoration of pre‐transformation levels of lysyl oxidase and transin mRNAs in phenotypic ras revertants

Abstract

Neoplastic transformation mediated by ras oncogenes is associated with deregulated expression of genes encoding, for example, various proteases, lysyl oxidase, and smooth-muscle alpha-actin. To define the role of these genes in the initiation or maintenance of the ras-transformed state, we compared their steady-state mRNA levels in two different sets of preneoplastic fibroblast lines, ras-transformed clones, and phenotypic revertants derived from them. Compared with the preneoplastic fibroblasts, the ras-transformed derivatives exhibited elevated levels of cathepsin L (major excreted protein), transin (stromelysin I, matrix metalloproteinase-3), and collagenase I (matrix metalloproteinase-1) mRNA but undetectable levels of lysyl oxidase mRNA. Partial restoration of lysyl oxidase transcription was observed in four of five phenotypic revertants derived from rat FE-8 and NIHpEJcl3 cells. The elevated levels of transin mRNA found in NIHpEJcl3 cells were diminished to the pretransformation level in interferon revertants but were not reduced in phenotypic rat FE-8 revertants expressing a high level of the ras oncoprotein. High steady-state levels of collagenase I mRNA were dependent on ras expression but were not closely associated with the transformed phenotype. High levels of cathepsin L mRNA were associated with neither high ras expression nor neoplastic transformation. The downregulation of smooth-muscle alpha-actin, characteristic of transformed cell lines, was not reversible in phenotypic revertants.

The Lysyl Oxidase LOX Is Absent in Basal and Squamous Cell Carcinomas and Its Knockdown Induces an Invading Phenotype in a Skin Equivalent Model

“…LOX has been discovered as a suppressor of the ras oncogene activity in fibroblasts (27,28). LOX expression was down-regulated in immortalized rat fibroblasts after transformation by activated H-ras (38,39). Other investigations reported a decrease of lysyl oxidase activity due to a decrease of LOX synthesis in malignantly transformed human cell lines (40), or LOX somatic mutations in colon cancer (41), or reduction of LOX mRNA expression in head and neck squamous cell carcinomas (19) and gastric cancer (16,17).…”

The class II tumour suppressor gene H-REV107-1 is a target of interferon-regulatory factor-1 and is involved in IFNγ-induced cell death in human ovarian carcinoma cells

“…An IRF-1 target gene identi®ed earlier is the lysyl oxidase gene (ras recision gene, rrg-1) (Tan et al, 1996). Lysyl oxidase is a secreted protein responsible for the maturation of the extracellular matrix and is implicated in the phenotypic reversion of HRAS-transformed NIH3T3 cells (Contente, 1990;Hajnal et al, 1993;Oberhuber et al, 1995). The two IRF-1 targets, lysyl oxidase and H-REV107-1, share several properties with respect to cellular transformation induced by RAS genes.…”

Transcriptional and translational downregulation of H-REV107, a class II tumour suppressor gene located on human chromosome 11q11-12

“…In addition, the anti-oncogenic capacity of interferon regulatory factor-1 may be mediated by the products of PKR (Kirchho et al, 1995) and H-rev142/lox (Tan et al, 1996) genes. H-rev142/lox and H-rev107 genes are characterized by an identical expression pattern in normal cells, HRAStransformed cells and in phenotypic revertants (Oberhuber et al, 1995;Hajnal et al, 1993Hajnal et al, , 1994. In view of the transformation-suppressing ability of both genes (Sers et al, 1997;Contente et al, 1990) and their modulation of expression by interferons (Oberhuber et al, 1995;Contente et al, 1990), it is tempting to speculate that H-rev107 genes contribute to the antitumour eects of interferons.…”