Targeting oncogenic microRNAs from the miR-371~373 and miR-302/367 clusters in malignant germ cell tumours causes growth inhibition through cell cycle disruption

Bailey, Shivani; Ferraresso, Marta; Alonso-Crisostomo, Luz; Ward, Dawn; Smith, Stephen; Nicholson, James C.; Saini, Harpreet; Enright, Anton J.; Scarpini, Cinzia G.; Coleman, Nicholas; Murray, Matthew J.

doi:10.1038/s41416-023-02453-1

Cited by 4 publications

(2 citation statements)

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“…This article focuses on the roles of miR-371 and miR-375 in various biological processes. miR-371 has been found to be overexpressed in TGCTs, regardless of age, location, or subtype [28]. Targeting miR-371 in these tumors has demonstrated to inhibit growth through cell cycle disruption [28].…”

Section: Microrna Signatures As Biomarkersmentioning

confidence: 99%

“…miR-371 has been found to be overexpressed in TGCTs, regardless of age, location, or subtype [28]. Targeting miR-371 in these tumors has demonstrated to inhibit growth through cell cycle disruption [28]. Moreover, miR-371 has been identified to suppress the initiation of colon cancer and metastatic colonization by inhibiting the TGFBR2-ID1 signaling axis [29].…”

Section: Microrna Signatures As Biomarkersmentioning

confidence: 99%

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MicroRNAs in Testicular Germ Cell Tumors: The Teratoma Challenge

Yodkhunnatham,

Pandit,

Puri

et al. 2024

IJMS

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Testicular germ cell tumors (TGCTs) are relatively common in young men, making accurate diagnosis and prognosis assessment essential. MicroRNAs (miRNAs), including microRNA-371a-3p (miR-371a-3p), have shown promise as biomarkers for TGCTs. This review discusses the recent advancements in the use of miRNA biomarkers in TGCTs, with a focus on the challenges surrounding the noninvasive detection of teratomas. Circulating miR-371a-3p, which is expressed in undifferentiated TGCTs but not in teratomas, is a promising biomarker for TGCTs. Its detection in serum, plasma, and, potentially, cystic fluid could be useful for TGCT diagnosis, surveillance, and monitoring of therapeutic response. Other miRNAs, such as miR-375-3p and miR-375-5p, have been investigated to differentiate between TGCT subtypes (teratoma, necrosis/fibrosis, and viable tumors), which can aid in treatment decisions. However, a reliable marker for teratoma has yet to be identified. The clinical applications of miRNA biomarkers could spare patients from unnecessary surgeries and allow for more personalized therapeutic approaches. Particularly in patients with residual masses larger than 1 cm following chemotherapy, it is critical to differentiate between viable tumors, teratomas, and necrosis/fibrosis. Teratomas, which mimic somatic tissues, present a challenge in differentiation and require a comprehensive diagnostic approach. The combination of miR-371 and miR-375 shows potential in enhancing diagnostic precision, aiding in distinguishing between teratomas, viable tumors, and necrosis. The implementation of miRNA biomarkers in TGCT care could improve patient outcomes, reduce overtreatment, and facilitate personalized therapeutic strategies. However, a reliable marker for teratoma is still lacking. Future research should focus on the clinical validation and standardization of these biomarkers to fully realize their potential.

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Section: Microrna Signatures As Biomarkersmentioning

confidence: 99%

Section: Microrna Signatures As Biomarkersmentioning

confidence: 99%

MicroRNAs in Testicular Germ Cell Tumors: The Teratoma Challenge

Yodkhunnatham,

Pandit,

Puri

et al. 2024

IJMS

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Replenishing co‐downregulated miR‐100‐5p and miR‐125b‐5p in malignant germ cell tumors causes growth inhibition through cell cycle disruption

Ferraresso,

Bailey,

Alonso‐Crisostomo

et al. 2024

Molecular Oncology

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MicroRNAs (miRNAs) are short, nonprotein‐coding RNAs, and their expression is dysregulated in malignant germ cell tumors (GCTs). Here, we investigated the causes and consequences of downregulated miR‐99a‐5p/miR‐100‐5p (functionally identical) and miR‐125b‐5p levels in malignant GCTs regardless of age, site, or subtype. Quantitative RT‐PCR was used to assess miR‐99a‐5p/miR‐100‐5p, miR‐125b‐5p, and associated gene expression in malignant GCT tissues/cell lines [seminoma (Sem), yolk sac tumor (YST), embryonal carcinoma (EC)]. Cells were treated with demethylating 5‐azacytidine and pyrosequencing was performed. Combination miR‐100‐5p/miR‐125b‐5p mimic replenishment was used to treat malignant GCT cells. Global messenger RNA (mRNA) targets of the replenished miRNAs were identified and Metascape used to study pathway effects. We found that expression levels of miR‐99a‐5p/miR‐100‐5p and miR‐125b‐5p, their respective pri‐miRNAs, and associated genes from chromosomes 11 and 21 (chr11/chr21) were downregulated and highly correlated in malignant GCT cells. Treatment with 5‐azacytidine caused upregulation of these miRNAs, with pyrosequencing revealing hypermethylation of their chr11/chr21 loci, likely contributing to miR‐100‐5p/miR‐125b‐5p downregulation. Combination miR‐100‐5p/miR‐125b‐5p mimic replenishment resulted in growth inhibition in Sem/YST cells, with miR‐100‐5p/miR‐125b‐5p mRNA targets enriched in downregulated genes, which were involved in cell cycle (confirmed by flow cytometry) and signaling pathways. Knockdown of the miR‐100‐5p/miR‐125b‐5p target tripartite motif containing 71 (TRIM71kd) recapitulated miR‐100‐5p/miR‐125b‐5p replenishment, with growth inhibition and cell cycle disruption of Sem/YST/EC cells. Further, replenishment led to reduced lin‐28 homolog A (LIN28A) levels and concomitant increases in let‐7 (MIRLET7B) tumor suppressor miRNAs, creating a sustained reversion of cell phenotype. In summary, combination miR‐100‐5p/miR‐125b‐5p mimic replenishment or TRIM71kd caused growth inhibition in malignant GCT cells via cell cycle disruption. Further studies are now warranted, including mimic treatment alongside conventional platinum‐based chemotherapy.

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