Modified miR-15a has therapeutic potential for improving treatment of advanced stage colorectal cancer through inhibition of BCL2, BMI1, YAP1 and DCLK1

Fesler, Andrew; Liu, Hua; Ju, Jingfang

doi:10.18632/oncotarget.23414

Cited by 46 publications

(72 citation statements)

References 59 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Over-expression of DCLK1 significantly increased chemoresistance of kidney cancer cells to the receptor tyrosine kinase inhibitors and mTOR inhibitors [50]. miR-15a might overcome chemoresistance of CRC stem cells to 5-FU through suppression of DCLK1 [51].…”

Section: Conclusion and Discussionmentioning

confidence: 97%

Doublecotin-like kinase 1 increases chemoresistance of colorectal cancer cells through the anti-apoptosis pathway

Jones

Mei

2019

Preprint

View full text Add to dashboard Cite

Colorectal cancer (CRC) is the third most common cancer diagnosed and the second leading cause of cancer-related deaths in the United States. About 50% of CRC patients relapsed after surgical resection and ultimately died of metastatic disease. Cancer stem cells (CSCs) are believed to be the primary reason for the recurrence of CRC. Specific stem cell marker, doublecortin-like kinase 1 (DCLK1) plays critical roles in initiating tumorigenesis, facilitating tumor progression, and promoting metastasis of CRC. It is up-regulated in CRC and upregulation of DCLK1 indicates poor prognosis. Whether DCLK1 is correlated with enhanced chemoresistance of CRC cells is unclear. Our research aims to reveal association of DCLK1 with chemoresistance of CRC cells and the underlying molecular mechanisms. In order to achieve our goal, we established stable DCLK1 over-expression cells (DCLK1+) using the HCT116 cells (WT). DCLK1+ and WT cells were treated with 5-Fluorouracil (5-Fu) at different doses for 24 or 48 hours. MTT assay was used to evaluate cell viability and IC 50 of 5-Fu was determined. Quantitative real time PCR was applied to determine gene expression of caspase-3 (casp-3), caspase-4 (casp-4), and caspase-10 (casp-10). Cleaved casp-3 expression was investigated using Western blot and immunofluorescence. Our results demonstrated that IC 50 of 5-Fu for the DCLK1+ cells was significantly higher than that of the WT cells for both 24 and 48hour treatment (P=0.002 and 0.048 respectively), indicating increased chemoresistance of the DCLK1+ cells. Gene expression of casp-3, casp-4, and casp-10 were significantly inhibited in the DCLK1+ cells after 5-Fu treatment compared to the WT cells (P=7.616e-08, 1.575e-05 and 5.307e-08, respectively). Cleaved casp-3 amount and casp-3 positive cells were significantly decreased in the DCLK1+ cells after 5-Fu treatment compared to the WT cells (P=0.015). In conclusion, our results demonstrated that DCLK1 overexpression enhanced the chemoresistance of CRC cells to 5-Fu treatment by suppressing gene expression of key caspases in the apoptosis pathway and activation of apoptosis pathway. DCLK1 can be an intriguing therapeutic target for the effective treatment of CRC patients.

show abstract

Section: Conclusion and Discussionmentioning

confidence: 97%

Doublecotin-like kinase 1 increases chemoresistance of colorectal cancer cells through the anti-apoptosis pathway

Jones

Mei

2019

Preprint

View full text Add to dashboard Cite

show abstract

“…miR-15a was initially discovered in CLL as a tumor suppressor 16 . miR-15a has also been extensively investigated in various tumor types as a tumor suppressor, targeting a number of important genes 13,17,26,27 . In this study we demonstrated miR-15a functions as a tumor suppressor in PDAC in vitro by inhibiting cell proliferation and impacts cell cycle control.…”

Section: Discussionmentioning

confidence: 99%

“…These findings along with the other targets we validated, demonstrate the unique potential of developing miR-15a mimic as a therapeutic agent as it can suppress a number of important targets to impact multiple pathways (Figure 7). In addition to the targets we have assessed in this study, previously identified targets of miR-15a such as BCL2 and DCLK1 have important functions in PDAC 17,23 . BLC2 expression is associated resistance to apoptosis and metastatic potential of PDAC and may be a potential therapeutic target 39,40 .…”

Section: Discussionmentioning

confidence: 99%

“…Twenty-four hours after transfection, 2000 cells per well were replated in a 96well plate. Cell viability was assessed on days 1, 3 and 6 post transfection using WST-1 dye (Roche, Basel, Switzerland) as previously described 17 .…”

Section: Cell Proliferationmentioning

confidence: 99%

“…Recent studies have demonstrated that miR-15a acts as tumor suppressor by regulating a number of key targets (such as BMI-1, BCL2, Yap-1, DCLK1 etc.) in gastric cancer, colorectal cancer and PDAC 12,13,17,18 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Functional significance and therapeutic potential of miR-15a mimic in pancreatic ductal adenocarcinoma

Guo

Fesler

Huang

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge.There is an urgent need to develop novel strategies to enhance survival and improve patient prognosis. microRNAs (miRNAs) play critical roles as oncogenes or tumor suppressors in the regulation of cancer development and progression. In this study, we demonstrate that low expression of miR-15a is associated with poor prognosis of PDAC patients. miR-15a expression is reduced in PDAC while closely related miR-16 expression remains relatively unchanged. miR-15a suppresses several important targets such as Wee1, Chk1, Yap-1, and BMI-1 causing cell cycle arrest and inhibiting cell proliferation. Ectopic expression of miR-15a sensitizes PDAC cells to gemcitabine reducing the IC 50 over 6.5-fold. To investigate the therapeutic potential of miR-15a, we used a modified miR-15a (5-FU-miR-15a) with uracil (U) residues in the guide strand replaced with 5-fluorouracil (5-FU). We demonstrated enhanced inhibition of PDAC cell proliferation by 5-FU-miR-15a compared to native miR-15a. In vivo we showed the therapeutic power of 5-FU-miR-15a alone or in combination with gemcitabine with near complete elimination of PDAC lung metastatic tumor growth. These results support the future development of 5-FU-miR-15a as a novel therapeutic agent as well as a prognostic biomarker in the clinical management of PDAC. Introduction:

show abstract

An in silico approach to identify and prioritize miRNAs target sites polymorphisms in colorectal cancer and obesity

et al. 2020

View full text Add to dashboard Cite

show abstract

Modified miR-15a has therapeutic potential for improving treatment of advanced stage colorectal cancer through inhibition of BCL2, BMI1, YAP1 and DCLK1

Cited by 46 publications

References 59 publications

Doublecotin-like kinase 1 increases chemoresistance of colorectal cancer cells through the anti-apoptosis pathway

Doublecotin-like kinase 1 increases chemoresistance of colorectal cancer cells through the anti-apoptosis pathway

Functional significance and therapeutic potential of miR-15a mimic in pancreatic ductal adenocarcinoma

An in silico approach to identify and prioritize miRNAs target sites polymorphisms in colorectal cancer and obesity

Contact Info

Product

Resources

About