Long Non-coding RNAs (lncRNAs) such as MALAT-1 Disrupt Regulatory Cell Mechanisms in the Pathogenesis of Ovarian Cancer.

Ali Imran Alwani

Introduction: Ovarian cancer is a leading cause of death caused by cancer in females1,2,3, and the stage of the disease determines the prognosis, with a 5-year survival rate for Stage IV cancer being around 20%4. As a result, there is a need for biomarkers that would be able to detect ovarian cancer early1,3. Various long non-coding RNAs (lncRNAs) such as MALAT-1 (Metastasis Associated Lung Adenocarcinoma Transcript 1), which are non-protein-coding RNA molecules that regulate gene transcription, are upregulated in ovarian cancer; however, their mechanisms in modulating disease progression are not completely understood2,5. Understanding these mechanisms could make lncRNAs valuable therapeutic targets and biomarkers1. Methods: Reverse transcriptase quantitative PCR (RT-qPCR) was used to determine the expression of MALAT-1 in cell cultures from patients with ovarian cancer6. A MALAT-1 knockdown was generated using a siRNA (Small interfering RNA) against MALAT-1 (siMALAT-1)6,7. A Wound Scratch Assay, the Annexin Apoptosis Detection kit, and propidium iodide were used to determine the rates of cell migration capability, apoptosis, and cell cycle arrest, respectively6,7. Western Blot analysis was used to determine the expression of phosphatidylinositol-3-kinases (PI3K), Protein Kinase B (Akt), and Matrix Metalloproteases 2 and 9 (MMP2 and MMP9) using antibodies against these proteins8. A LASSO (least absolute shrinkage and selection operator) penalized regression test was used to characterize a six-lncRNA signature, including MALAT-1, which divided 311 patients into “high risk” and “low risk” groups based on the predicted recurrence risk9. Results: From RT-qPCR, it was determined that MALAT-1 is over-expressed in ovarian cancer cells by more than four-fold (p = 0.001)6. From the siMALAT-1 knockdown assays, it was found that the MALAT-1 knockdown is associated with two times decreased cell migration capability, ten-fold increase in apoptosis, and increased G1 cell cycle arrest (p < 0.05)6,7. From the Western Blot analysis, it was found that the MALAT-1 knockdown is associated with a greater than two-fold decreased expression of PI3K, Akt, and MMP2 and MMP9 (p < 0.05)8. The six-lncRNA signature test showed that the “low-risk” patient group had a significantly increased number of disease free days, around 200 days, before recurrence compared to the “high-risk” group (p < 0.0001)9. Conclusion: Various lncRNAs such as MALAT-1 are upregulated in ovarian cancer and are involved in promoting tumor proliferation6,7,8. These lncRNAs could act as potential therapeutic targets and biomarkers that could detect high-risk patients early based on genetic analysis, which could significantly improve prognoses in patients with ovarian cancer1,9.

 

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