An Alternatively Spliced p62 Isoform Confers Resistance to Chemotherapy in Breast Cancer

Abstract

Resistance to chemotherapy remains a major obstacle to the successful treatment of breast cancer. More than 80% of patients who receive neoadjuvant chemotherapy (NAC) do not achieve a pathological complete response. In this study, we report a novel p62 mRNA isoform with a short 3′-UTR (p62-SU, 662-nt) that is associated with chemoresistance in breast cancer cells and tissue specimens. The p62 mRNA isoform was identified by RNA sequencing with qRT-PCR, 3′-RACE, and northern blot analysis. In vitro and in vivo, ectopic expression of p62-SU promoted breast cancer cell proliferation, migration, invasion, and chemoresistance compared with the p62 mRNA isoform with a full-length 3′-UTR (p62-LU, 1,485-nt). Mechanistically, CPSF1 modulated the 3′-UTR of p62 through alternative polyadenylation. In addition, p62-SU escaped miR-124-3p-mediated repression and upregulated p62-SU protein expression, thereby inducing p62-dependent chemoresistance. These data suggest that a CPSF1-p62-miR-124-3p signaling axis is responsible for reduced sensitivity of breast cancer to chemotherapy.

Beyond self‑eating: Emerging autophagy‑independent functions for the autophagy molecules in cancer (Review)

“…As aforementioned, an ATG16L1 variant (T600A) stimulates an anti-tumor immune response and is associated with a good prognosis (99). SQSTM1 is expressed in several variants: N-Ter truncated isoform lacking the domain responsible for SQSTM1 oligomerization and autophagic cargo sorting ability (146); splice variant affecting the p62/Keap1/NRF2 axis (147) and SQSTM1 3' untranslated region-truncated variant associated with aggressiveness and resistance to therapy in patients with breast cancer (148). Therefore, it would be of interest to determine whether these different AMMs isoforms exhibit autophagy-independent functions.…”

Analysis of Breast Cancer Differences between China and Western Countries Based on Radiogenomics

“…To reduce the image quality difference between cases in multiple institutions, we selected MRI images obtained by the same scanner, and a total of 91 patients were obtained; Downloaded the gene expression RNAseq data from the GDC TCGA Breast Cancer dataset from UCSC Xena [ 32 ] ( accessed on 1 November 2021). These transcriptome data correspond to patients with imaging data; Downloaded GSE116180 [ 33 ], GSE197894 [ 34 ], and GSE198545 [ 35 ] from the GEO database as validation datasets. …”

“…Downloaded GSE116180 [ 33 ], GSE197894 [ 34 ], and GSE198545 [ 35 ] from the GEO database as validation datasets.…”

De novo detection of somatic variants in high-quality long-read single-cell RNA sequencing data

“…However, relying solely on gene-level expression may be insufficient, as cells can express different isoforms, resulting in different phenotypes (Ding et al 2020). Isoform-specific cancer resistance can be induced, for example, through alternative splicing (Mitra et al 2009; Chen et al 2022), polyadenylation (Guo et al 2022), or large genomic rearrangements leading to gene fusions (Amatu et al 2016; Lei et al 2018; (Cesi et al 2018). These interlinked features need to be examined together, thus requiring complete isoform coverage (Foord et al 2023).…”