Targeting PVT1 Exon 9 Re-Expresses Claudin 4 Protein and Inhibits Migration by Claudin—Low Triple Negative Breast Cancer Cells

Abstract

PVT1 is a long non-coding RNA transcribed from a gene located at the 8q24 chromosomal region that has been implicated in multiple cancers including breast cancer (BC). Amplification of the 8q24 chromosomal region is a common event in BC and is associated with poor clinical outcomes. Claudin–low (CL) triple negative breast cancer (TNBC) is a subtype of BC with a particularly dismal outcome. We assessed PVT1 exon 9 expression in the T47D estrogen receptor positive BC cell line, and in the MDA MB 468 and MDA MB 231 TNBC cell lines, followed by the assessment of the expression of claudins 1, 3, 4 and 7, in MDA MB 468 and MDA MB 231 (TNBC) cells. We found that MDA MB 231 TNBC cells significantly express less claudin 1, 3, 4, and 7 than MDA MB 468 TNBC cells. PVT1 exon 9 is significantly upregulated in MDA MB 231 CL TNBC cells, and significantly downregulated in MDA MB 468 claudin high (CH) TNBC cells, in comparison to T47D estrogen receptor positive BC cells. We then analyzed the functional consequences of siRNA targeting of PVT1 exon 9 expression in the MDA MB 231 CL TNBC cells. Notably, siRNA targeting of PVT1 exon 9 expression in the MDA MB 231 CL TNBC cells led to a significant reduction in migration and the re-expression of claudin 4. Taken together, our data indicate that PVT1 exon 9 regulates claudin 4 expression and migration in CL TNBC cells, and may have clinical implications in CL TNBC.

Protein profiling reveals potential isomiR-associated cross-talks among RNAs in cholangiocarcinoma

“…Many of these lncRNAs showed association with other RNAs. CASC2 acts as a tumor suppressor and potentially as a competing endogenous RNA for miR-21, and plays important role in IDH1 wild type glioma pathogenesis and patients' outcomes [51] , LINC00265 can promote colorectal tumorigenesis via ZMIZ2 and USP7-mediated stabilization of beta-catenin [52] , and PVT1 exon 9 regulates claudin 4 expression and migration in CL TNBC cells, and may have clinical implications in CL TNBC [53] . A pan-cancer analysis showed that some were also deregulated in other cancer types ( Fig.…”

lncRNA PVT1: a novel oncogene in multiple cancers

“…A year later, Levine et al. [ 145 ] suggested that PVT1 exon 9 may regulate BC cell migration by reducing claudin 4 expression.…”

“…Subsequently, El-Fattah et al [144] revealed the efficacy of PVT1, HOTAIR, NEAT1, PAI-1, and OPN as diagnostic biomarkers in BC. A year later, Levine et al [145] suggested that PVT1 exon 9 may regulate BC cell migration by reducing claudin 4 expression.…”

An Approach to Cell Motility as a Key Mechanism in Oncology

“…Two contributions in this Special Issue deal with breast cancer [ 3 , 4 ], the leading cause of cancer-related death in European women. In their work, Panzetta et al [ 3 ] study how the extracellular matrix stiffness interferes in the adhesion and migration properties of two different mammary cell lines under the exposure of two different X-ray doses.…”

“…This cellular response, called durotaxis and originally described in fibroblasts, observed in mammary cell lines reproduces the results obtained in previous experiments performed in unicellular organisms ( Dictyostelium discoideum and Caenorhabditis elegans , among others) and melanoma cell lines, as it will be mentioned elsewhere in this collection [ 5 ]. On the other hand, Levine and Ogunwobi [ 4 ] focus their work on triple-negative breast cancer, a subset of around 10% of mammary carcinomas which pursues an especially aggressive clinical course. More specifically, they have centered their research on one of the six subtypes of this tumor variant, that is, the so-called claudin-low triple-negative breast carcinoma.…”