Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells

Chirshev, Evgeny; Suzuki, Tise; Wang, Hanmin; Nguyen, Anthony; Hojo, Nozomi; Sanderman, Linda; Mirshahidi, Saied; Ioffe, Yevgeniya; Unternaehrer, Juli

doi:10.3390/cancers13184617

Cited by 8 publications

(7 citation statements)

References 86 publications

(113 reference statements)

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“…Importantly, compared to all the other Let-7 family, Let-7i had the strongest correlation with tumoural immune pathways in the > 600 human tumours examined in this study, highlighting its utility in enhancing anti-tumour immunity in HGSC. This complements well with the previously reported role of Let-7i in sensitising cancer cells to PARPi and platinum-based therapies in HGSC [ 59 , 60 ]. Future work should focus on validating Let-7i’s impact on tumour immunity in other murine models of ovarian cancer as well as its ability to generate tumour antigen-specific immune response.…”

Section: Discussionsupporting

confidence: 91%

“…Specifically, for Let-7i, previous studies have found that it reduces cancer cell proliferation and migration through downregulating ERK3 expression in head and neck cancer, as well as HGMCA1 expression in bladder cancer [ 57 , 58 ]. Specifically in ovarian cancer, Let-7i upregulation decreased stemness and self-renewal, reduced anchorage-independent growth, decreased functional phenotypes associated with metastasis and increased sensitivity to PARPi and platinum-based therapies [ 59 , 60 ]. We are the first to assess the in vivo effects of Let-7i therapeutic delivery in any tumour model to our knowledge and found Let-7i has a significant therapeutic effect on ovarian tumours.…”

Section: Discussionmentioning

confidence: 99%

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Let-7i enhances anti-tumour immunity and suppresses ovarian tumour growth

Wilkinson,

Chen,

Coleborn

et al. 2024

Cancer Immunol Immunother

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Cancer immunotherapy has seen significant success in the last decade for cancer management by enhancing endogenous cancer immunity. However, immunotherapies developed thus far have seen limited success in the majority of high-grade serous carcinoma (HGSC) ovarian cancer patients. This is largely due to the highly immunosuppressive tumour microenvironment of HGSC and late-stage identification. Thus, novel treatment interventions are needed to overcome this immunosuppression and complement existing immunotherapies. Here, we have identified through analysis of > 600 human HGSC tumours a critical role for Let-7i in modulating the tumoural immune network. Tumoural expression of Let-7i had high positive correlation with anti-cancer immune signatures in HGSC patients. Confirming this role, enforced Let-7i expression in murine HGSC tumours resulted in a significant decrease in tumour burden with a significant increase in tumour T cell numbers in tumours. In concert with the improved tumoural immunity, Let-7i treatment also significantly increased CD86 expression in antigen presenting cells (APCs) in the draining lymph nodes, indicating enhanced APC activity. Collectively, our findings highlight an important role of Let-7i in anti-tumour immunity and its potential use for inducing an anti-tumour effect in HGSC.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Let-7i enhances anti-tumour immunity and suppresses ovarian tumour growth

Wilkinson,

Chen,

Coleborn

et al. 2024

Cancer Immunol Immunother

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“…Let-7a targets IGF-2, which is oncogenic in NSCLC tissue [25]; increased expression of NEAT1 downregulates let-7a, removing the miRNA block on IGF-2 expression, and resulting in increased NSCLC cell proliferation, migration and invasion [25]. Similarly, in epithelial ovarian cancer, let-7 also downregulates IGF-1, possibly contributing to a less aggressive phenotype [26] (Fig. 1).…”

Section: Let-7mentioning

confidence: 99%

“…LncRNA NEAT1 increases oncogenic IGF1R signaling by competing against miRNA Let-7a, which targets IGF-2 [25]. Let-7 also potentially downregulates IGF-1 [26]. LncRNA NR2F1-AS1 can also lead to IGF1R activation by sponging miR-338-3p, which downegulates IGF-1 [27].…”

Section: H19mentioning

confidence: 99%

Noncoding RNA actions through IGFs and IGF binding proteins in cancer

Kerr

Baxter

2022

Oncogene

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The insulin-like growth factors (IGFs) and their regulatory proteins—IGF receptors and binding proteins—are strongly implicated in cancer progression and modulate cell survival and proliferation, migration, angiogenesis and metastasis. By regulating the bioavailability of the type-1 IGF receptor (IGF1R) ligands, IGF-1 and IGF-2, the IGF binding proteins (IGFBP-1 to -6) play essential roles in cancer progression. IGFBPs also influence cell communications through pathways that are independent of IGF1R activation. Noncoding RNAs (ncRNAs), which encompass a variety of RNA types including microRNAs (miRNAs) and long-noncoding RNAs (lncRNAs), have roles in multiple oncogenic pathways, but their many points of intersection with IGF axis functions remain to be fully explored. This review examines the functional interactions of miRNAs and lncRNAs with IGFs and their binding proteins in cancer, and reveals how the IGF axis may mediate ncRNA actions that promote or suppress cancer. A better understanding of the links between ncRNA and IGF pathways may suggest new avenues for prognosis and therapeutic intervention in cancer. Further, by exploring examples of intersecting ncRNA-IGF pathways in non-cancer conditions, it is proposed that new opportunities for future discovery in cancer control may be generated.

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“…Furthermore, ovarian cancer has been characterized as a largely heterogenous disease, resulting in varying effectiveness of currently available therapies 4,5 . Previously, our lab has focused on the characterization of a variety of patient-derived high-grade serous ovarian carcinoma (HGSOC) samples 6,7 . As the most aggressive subtype of ovarian cancer, the HGSOC samples indicated a large distribution of growth rate, morphology, gene and protein expression, and response to commonly used therapies, like cisplatin, a platinum-based agent that forms adducts with DNA, and olaparib, a poly (ADP-ribose) polymerase inhibitor (PARPi) 6 .…”

Section: Introductionmentioning

confidence: 99%

Modeling platinum resistance in a stem-like patient-derived ovarian cancer sample

Suzuki,

Conant,

Jung

et al. 2024

Preprint

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Background Chemoresistance and tumor recurrence remain a significant challenge in ovarian cancer. Particularly in the context of platinum resistance, many mechanisms have been identified, including the activation of cellular processes like epithelial-mesenchymal transition (EMT), which generates cells with stemness characteristics. Current models of platinum resistance are limited or not adequate representations of the heterogeneity of the disease. Thus, to advance our understanding of chemoresistance in the context of cancer stem cells (CSC) in ovarian cancer, this study aims to develop an effective model for cisplatin resistance using a patient-derived cancer stem-like sample. Methods PDX4, a patient-derived cancer cell line with stem-like properties, was exposed to increasing concentrations of cisplatin in vitro in parallel with vehicle treated cells. Once chemoresistance was established and confirmed, the resistance model was validated through comprehensive molecular profiling through RNA- and miRNA-sequencing, followed by the assessment of alterations in cell morphology, protein expression, and functional properties in the context of EMT and cancer stemness. Moreover, we explored potential signaling pathways involved in cisplatin resistance in these stem-like cancer cells. Results Our findings reveal the presence of distinct molecular signatures and phenotypic changes in cisplatin resistant PDX4 compared to their sensitive counterparts. Furthermore, we observed that chemoresistance was not inherently linked with increased stemness. In fact, although resistant cells expressed a combination of EMT and stemness markers, functional assays revealed that they were less proliferative, migratory, and clonogenic. JAK-STAT, hypoxia, and PI3K signaling pathways were enriched in these cells, indicating the activation of pathways that assist in DNA damage tolerance and cellular stress management. Conclusion This novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapeutic strategies tailored to combat resistance in stem-like ovarian cancer.

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Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells

Cited by 8 publications

References 86 publications

Let-7i enhances anti-tumour immunity and suppresses ovarian tumour growth

Let-7i enhances anti-tumour immunity and suppresses ovarian tumour growth

Noncoding RNA actions through IGFs and IGF binding proteins in cancer

Modeling platinum resistance in a stem-like patient-derived ovarian cancer sample

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