The Tumor-Specific Expression of L1 Retrotransposons Independently Correlates with Time to Relapse in Hormone-Negative Breast Cancer Patients

Berrino, Enrico; Miglio, Umberto; Bellomo, Sara E.; Debernardi, Carla; Bragoni, Alberto; Petrelli, Annalisa; Cascardi, Eliano; Giordano, Silvia; Montemurro, Filippo; Marchiò, Caterina; Venesio, Tiziana; Sapino, Anna

doi:10.3390/cells11121944

Cited by 2 publications

(1 citation statement)

References 56 publications

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“…To investigate the gene expression of L1-MET, quantitative Real-Time PCR (qRT-PCR) was used, using reported primers and PCR conditions (Miglio, et al 2018). Relative expression quanti cation (RQ) was calculated according to the following formula in Berrino, et al (2022), using GAPDH as endogenous control: RQ = 2−(ΔCt) where ΔCt = (Ct L1-MET − Ct GAPDH).…”

Section: Rna Extraction and Qrt-pcr Analysismentioning

confidence: 99%

The silencing of the L1-MET chimeric transcript activates cancer cell death program and inhibits the expression of crucial oncoproteins in lung cancer cells

Miglio,

Berrino,

Avanzato

et al. 2023

Preprint

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Background Among the antisense chimeric sequences generated by intragenic long interspersed nuclear elements (LINE1s), L1-MET transcript, within MET oncogene, is of particular interest since its expression, activated by promoter hypomethylation, has been associated with the acquisition of cancer phenotype. L1-MET can originate several isoforms, but it is unable to form stable proteins. Presently, its biological functions remain unknown. Methods To investigate the role of L1-MET, we silenced its expression on selected lung and breast cancer cells, characterized by variable levels of L1-MET and MET mRNA, using specifically-modified targeting antisense oligonucleotides. In addition to viability and apoptotic rate, the transfected cells were compared for their gene expression profiles and the protein level of identified downregulated cancer genes. Results Besides a considerable decrease of cell viability and increase of apoptosis, transiently transfected cancer cells partly rewrote their gene expression profiles, with an effect related to the L1-MET/ MET mRNA level and the type of cells, being particularly strong in lung cancer cells. In particular, MET and EGFR genes, activated in EBC1 lung cancer cells, but at the steady-state level in the other tested cell lines, showed a significant downregulation of MET and EGFR oncoproteins, with a specific loss of the AKT phosphorylation and a decrease of phospho-ERK, in the case of EBC1 cells. No effects were evidenced in non-transformed fibroblasts and human lymphocytes, used as controls. Conclusions Our results clearly demonstrate the ability of L1-MET to interfere with the expression of MET and EGFR oncoproteins in selected cancer cells. The expression of L1-MET, strictly limited to transformed cells, makes its silencing an ideal approach to induce tumor cells to death and a potential inhibitor of crucial oncoproteins on which cancer cells rely for their survival and proliferation, such as lung cancer cells.

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Section: Rna Extraction and Qrt-pcr Analysismentioning

confidence: 99%

The silencing of the L1-MET chimeric transcript activates cancer cell death program and inhibits the expression of crucial oncoproteins in lung cancer cells

Miglio,

Berrino,

Avanzato

et al. 2023

Preprint

Self Cite

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Prospects for breast cancer immunotherapy using microRNAs and transposable elements as objects

Mustafin

2024

Exploration of Targeted Anti-Tumor Therapy

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One of the directions in treatment of chemoresistant breast cancer (BC) may include new methods of activating the immune response against tumor cells. Clinically used checkpoint inhibition using antibodies to PD-1 and PD-L1 works in some patients, but the lack of biomarkers means number of respondents is low. The possibility of combining this method with chemotherapy is limited by an increased risk of toxic liver damage, development of immune-related pneumonitis, and thyroid dysfunction. This article includes introduction into the clinic of new methods of immunotherapy for BC, among which epigenetic activation of retroelements, double-stranded transcripts of which stimulate the interferon response against the tumor, is promising. For this purpose, inhibitors of DNA methyltransferase*, histone deacetylase* and histone methyltransferase* are used (* subtitles in the main text). Their antitumor effect is also mediated by removal of repressive epigenetic marks from tumor suppressor genes. However, numerous studies have proven the role of retroelements in the carcinogenesis of various malignant neoplasms, including BC. Moreover, endogenous retroviruses HERV-K and LINE1 retrotransposons are planned to be used as diagnostic biomarkers for BC. Therefore, a rational approach to using viral mimicry in antitumor therapy of BC may be the simultaneous suppression of specific retrotransposons (drivers for carcinogenesis) using reverse transcriptase inhibitors and silencing of specific transposons involved in carcinogenesis using complementary microRNAs. To determine possible pathways of influence in this direction, 35 specific transposon-derived microRNAs* changes in BC were identified, which can become guides for targeted therapy of BC.

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The Tumor-Specific Expression of L1 Retrotransposons Independently Correlates with Time to Relapse in Hormone-Negative Breast Cancer Patients

Cited by 2 publications

References 56 publications

The silencing of the L1-MET chimeric transcript activates cancer cell death program and inhibits the expression of crucial oncoproteins in lung cancer cells

The silencing of the L1-MET chimeric transcript activates cancer cell death program and inhibits the expression of crucial oncoproteins in lung cancer cells

Prospects for breast cancer immunotherapy using microRNAs and transposable elements as objects

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