Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis

Hossian, A K M Nawshad; Muthumula, Chandra Mohan Reddy; Sajib, Sanaullah; Tullar, Paul; Stelly, April M; Briski, Karen P.; Mikelis, Constantinos M.; Matthaiolampakis, George

doi:10.3791/59460

Cited by 7 publications

(13 citation statements)

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“…miR-based therapeutics have emerged as promising mRNA regulators for cancer treatment, capable to control multiple cell functions ( 33 ). In particular, the miR combination of miR-143 and miR-506 inhibits the cell cycle progression in two phase transitions, through downregulation of CDK1, CDK4 and CDK6, and causes strong apoptotic activity, as we recently reported ( 34 , 35 ). Here, we report on the combinatorial treatment effect of these two miRs downregulating CDK1, CDK4 and CDK6, and inhibiting cell growth in LC and PC cells.…”

Section: Introductionsupporting

confidence: 55%

“…We transfected the H358 and H1975 cells with the combinatorial treatment of miR-143/506 at 100 nM using Lipofectamine, and analyzed the CDK1, CDK4 , and CDK6 gene expression, using qPCR at 24 and 48 h post-transfection. The chosen two cell lines carry driver mutations that can complement and correlate with our previously published work on A549 cells ( 34 , 35 ). The treatment downregulated these three genes compared to the untreated or scramble-treated (negative control) groups in both of the cell lines ( Fig.…”

Section: Resultsmentioning

confidence: 95%

“…MicroRNAs (miRNAs/miRs) are critical regulators of mRNA expression, and various diseases, including cancer, have been associated with miR dysregulation ( 47 , 48 ). We recently reported on two miRs, miR-143 and miR-506, previously recognized with essential functions in cancer and other diseases ( 34 , 35 , 49 , 50 ). miR-143 has base-pair complementarity with the 3′-UTR region of cyclin-dependent kinase 1 (CDK1), and miR-506 has base-pair complementarity with the 3′-UTR regions of CDK4 and CDK6 ( 35 , 51 , 52 ).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, both CDK1 and CDK4 were higher in cancer samples compared to normal samples, and more importantly, protein expression for CDK1 and CDK4 vs. survival in patients with LC adenocarcinomas indicated a negative correlation between CDK1 and CDK4 expression and survival. We recently reported that miR-143 and miR-506 have CDK1 and CDK4 mRNAs as their predicted targets, respectively ( 34 , 35 ). These data align with previously reported work on these genes ( 13 , 32 ).…”

Section: Discussionmentioning

confidence: 99%

“…We performed the cell cycle analysis using a flow cytometric technique, as previously described ( 34 , 35 ). Briefly, we stained cells with propidium iodide (PI) (MP Biomedicals, LLC) and analyzed the cells using a BD FACSCalibur Flow Cytometer, with Cellquest Pro software (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

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Combination of miR‑143 and miR‑506 reduces lung and pancreatic cancer cell growth through the downregulation of cyclin‑dependent kinases

2021

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Lung cancer (LC) and pancreatic cancer (PC) are the first and fourth leading causes of cancer-related deaths in the US. Deregulated cell cycle progression is the cornerstone for rapid cell proliferation, tumor development, and progression. Here, we provide evidence that a novel combinatorial miR treatment inhibits cell cycle progression at two phase transitions, through their activity on the CDK4 and CDK1 genes. Following transfection with miR-143 and miR-506, we analyzed the differential gene expression of CDK4 and CDK1 , using qPCR or western blot analysis, and evaluated cell cycle inhibition, apoptosis and cytotoxicity. The combinatorial miR-143/506 treatment downregulated CDK4 and CDK1 levels, and induced apoptosis in LC cells, while sparing normal lung fibroblasts. Moreover, the combinatorial miR treatment demonstrated a comparable activity to clinically tested cell cycle inhibitors in inhibiting cell cycle progression, by presenting substantial inhibition at the G 1 /S and G 2 /M cell cycle transitions. More importantly, the miR-143/506 treatment presented a broader application, effectively downregulating CDK1 and CDK4 levels, and reducing cell growth in PC cells. These findings suggest that the miR-143/506 combination acts as a promising approach to inhibit cell cycle progression for cancer treatment with minimal toxicity to normal cells.

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Section: Introductionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 95%