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MiR-106b induces cell radioresistance via the PTEN/PI3K/AKT pathways and p21 in colorectal cancer.

Zheng L, Zhang Y, Liu Y, Zhou M, Lu Y, Yuan L, Zhang C, Hong M, Wang S, Li X - J Transl Med (2015)

Bottom Line: Correspondingly, knocking down miR-106b in SW480 yielded the opposite effect.Restoring the expression of PTEN or p21 in stably miR-106b-overexpressed cells could rescue the effect of miR-106b on cell radioresistance.These observations illustrated that miR-106b could induce cell radioresistance by directly targeting PTEN and p21, this process was accompanied by tumour-initiating cell capacity enhancement, which is universally confirmed to be associated with radioresistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. 147938636@qq.com.

ABSTRACT

Background: Radioresistance is a challenge in the treatment of patients with colorectal cancer (CRC). Individuals display different therapeutic responses to preoperative radiotherapy, and the need of targeted therapies is urgent. MicroRNAs (miRNAs) are involved in essential biological activities, including chemoresistance and radioresistance. Several research studies have indicated that miRNA played an important role in sensitizing cells to ionizing radiation (IR). MiR-106b, a member of the miR-106b-25 cluster, is frequently dysregulated in many human cancers, including CRC. However, the function of miR-106b in radioresistance is currently poorly understood.

Methods: A series of in vitro and in vivo studies were performed to investigate the roles of miR-106b on cell radioresistance in CRC.

Results: We found overexpression of miR-106b could induce resistance to IR in vitro and in vivo in SW620 cells. Correspondingly, knocking down miR-106b in SW480 yielded the opposite effect. In addition, overexpression of miR-106b could enhance the tumour-initiating cell capacity without or with IR condition, such as the colony sphere formation capacity and the upregulation of stemness-related genes (CD133, Sox2). We further identified PTEN and p21 as novel direct targets of miR-106b by using target prediction algorithms and a luciferase assay. Overexpression of miR-106b reduced the expression of PTEN and p21 and increased the expression of p-AKT, which is a downstream of PTEN. Restoring the expression of PTEN or p21 in stably miR-106b-overexpressed cells could rescue the effect of miR-106b on cell radioresistance. Together, the acquisition of tumour-initiating cell capacity endowed CRC cells with the potential of resistance to irradiation.

Conclusions: These observations illustrated that miR-106b could induce cell radioresistance by directly targeting PTEN and p21, this process was accompanied by tumour-initiating cell capacity enhancement, which is universally confirmed to be associated with radioresistance. Our data suggested that miR-106b at least partly induces cell radioresistance in CRC.

No MeSH data available.


Related in: MedlinePlus

PTEN expression is inversely related to that of miR-106b in colorectal cancer. a A western blot for the PTEN protein was performed in colorectal cancer cell lines. b qRT-PCR on 15 colorectal cancer patients. The association between miR-106b and PTEN mRNA for the 15 subjects in the tumour class and for the paired 15 subjects in the normal class was statistically calculated using the Spearman correlation coefficient (p = 0.006, Spearman’s r = −0.491). The Spearman correlation indicated an inverse relation between miR-106b and PTEN mRNA in the normal and tumour samples.
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Fig5: PTEN expression is inversely related to that of miR-106b in colorectal cancer. a A western blot for the PTEN protein was performed in colorectal cancer cell lines. b qRT-PCR on 15 colorectal cancer patients. The association between miR-106b and PTEN mRNA for the 15 subjects in the tumour class and for the paired 15 subjects in the normal class was statistically calculated using the Spearman correlation coefficient (p = 0.006, Spearman’s r = −0.491). The Spearman correlation indicated an inverse relation between miR-106b and PTEN mRNA in the normal and tumour samples.

Mentions: We found an inverse correlation between miR-106b RNA expression and PTEN protein expression in colorectal cancer cell lines of different differentiation degrees (Fig. 5a). PTEN is one of the most frequent tumour suppressors in human cancers [26, 27], and miR-106b is upregulated in colorectal cancer tissues. Thus, we evaluated the endogenous levels of miR-106b and PTEN using real-time quantitative RT-PCR (qRT-PCR) in primary colorectal cancer tissues (Additional file 8: Figure S4). We found that the expression levels of miR-106b and PTEN significantly correlated in colorectal tissues (p = 0.006, Spearman’s r = −0.491) (Fig. 5b). The results showed that the expression of miR-106b inversely correlated with PTEN in colorectal cancer and normal colonic tissues, which further supported the finding that PTEN is a direct target of miR-106b in vivo.Fig. 5


MiR-106b induces cell radioresistance via the PTEN/PI3K/AKT pathways and p21 in colorectal cancer.

Zheng L, Zhang Y, Liu Y, Zhou M, Lu Y, Yuan L, Zhang C, Hong M, Wang S, Li X - J Transl Med (2015)

PTEN expression is inversely related to that of miR-106b in colorectal cancer. a A western blot for the PTEN protein was performed in colorectal cancer cell lines. b qRT-PCR on 15 colorectal cancer patients. The association between miR-106b and PTEN mRNA for the 15 subjects in the tumour class and for the paired 15 subjects in the normal class was statistically calculated using the Spearman correlation coefficient (p = 0.006, Spearman’s r = −0.491). The Spearman correlation indicated an inverse relation between miR-106b and PTEN mRNA in the normal and tumour samples.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522974&req=5

Fig5: PTEN expression is inversely related to that of miR-106b in colorectal cancer. a A western blot for the PTEN protein was performed in colorectal cancer cell lines. b qRT-PCR on 15 colorectal cancer patients. The association between miR-106b and PTEN mRNA for the 15 subjects in the tumour class and for the paired 15 subjects in the normal class was statistically calculated using the Spearman correlation coefficient (p = 0.006, Spearman’s r = −0.491). The Spearman correlation indicated an inverse relation between miR-106b and PTEN mRNA in the normal and tumour samples.
Mentions: We found an inverse correlation between miR-106b RNA expression and PTEN protein expression in colorectal cancer cell lines of different differentiation degrees (Fig. 5a). PTEN is one of the most frequent tumour suppressors in human cancers [26, 27], and miR-106b is upregulated in colorectal cancer tissues. Thus, we evaluated the endogenous levels of miR-106b and PTEN using real-time quantitative RT-PCR (qRT-PCR) in primary colorectal cancer tissues (Additional file 8: Figure S4). We found that the expression levels of miR-106b and PTEN significantly correlated in colorectal tissues (p = 0.006, Spearman’s r = −0.491) (Fig. 5b). The results showed that the expression of miR-106b inversely correlated with PTEN in colorectal cancer and normal colonic tissues, which further supported the finding that PTEN is a direct target of miR-106b in vivo.Fig. 5

Bottom Line: Correspondingly, knocking down miR-106b in SW480 yielded the opposite effect.Restoring the expression of PTEN or p21 in stably miR-106b-overexpressed cells could rescue the effect of miR-106b on cell radioresistance.These observations illustrated that miR-106b could induce cell radioresistance by directly targeting PTEN and p21, this process was accompanied by tumour-initiating cell capacity enhancement, which is universally confirmed to be associated with radioresistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. 147938636@qq.com.

ABSTRACT

Background: Radioresistance is a challenge in the treatment of patients with colorectal cancer (CRC). Individuals display different therapeutic responses to preoperative radiotherapy, and the need of targeted therapies is urgent. MicroRNAs (miRNAs) are involved in essential biological activities, including chemoresistance and radioresistance. Several research studies have indicated that miRNA played an important role in sensitizing cells to ionizing radiation (IR). MiR-106b, a member of the miR-106b-25 cluster, is frequently dysregulated in many human cancers, including CRC. However, the function of miR-106b in radioresistance is currently poorly understood.

Methods: A series of in vitro and in vivo studies were performed to investigate the roles of miR-106b on cell radioresistance in CRC.

Results: We found overexpression of miR-106b could induce resistance to IR in vitro and in vivo in SW620 cells. Correspondingly, knocking down miR-106b in SW480 yielded the opposite effect. In addition, overexpression of miR-106b could enhance the tumour-initiating cell capacity without or with IR condition, such as the colony sphere formation capacity and the upregulation of stemness-related genes (CD133, Sox2). We further identified PTEN and p21 as novel direct targets of miR-106b by using target prediction algorithms and a luciferase assay. Overexpression of miR-106b reduced the expression of PTEN and p21 and increased the expression of p-AKT, which is a downstream of PTEN. Restoring the expression of PTEN or p21 in stably miR-106b-overexpressed cells could rescue the effect of miR-106b on cell radioresistance. Together, the acquisition of tumour-initiating cell capacity endowed CRC cells with the potential of resistance to irradiation.

Conclusions: These observations illustrated that miR-106b could induce cell radioresistance by directly targeting PTEN and p21, this process was accompanied by tumour-initiating cell capacity enhancement, which is universally confirmed to be associated with radioresistance. Our data suggested that miR-106b at least partly induces cell radioresistance in CRC.

No MeSH data available.


Related in: MedlinePlus