Upregulation of microRNA‐135b and microRNA‐182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3K/AKT pathway

Liu, Bing; Liu, Yanfeng; Zhao, Lifen; Pan, Yue; Shan, Yujia; Yang, Li; Li, Jia

doi:10.1002/mc.22710

Cited by 76 publications

(54 citation statements)

References 38 publications

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“…WNT/β-catenin, RAS/ERK/ MAPK, JAK/STAT, NOTCH), we believe ncRNA may also play a role in the resistance of PI3K inhibitors [194][195][196][197][198][199]. Not surprisingly, more and more researches have suggested that deviant ncRNA expression is powerfully concerned about tumor drug resistance [200][201][202][203][204][205][206][207][208]. Recent studies have indicated potential mechanism of acquired resistance to dual PI3K/mTOR inhibitors, including elevated glycolysis accompanied with depletion of mitochondrial DNA, and upregulated DNA methyltransferases which Reduce PTEN and PPP2R2B expression [209,210].…”

Section: Resistancesmentioning

confidence: 99%

Targeting PI3K in cancer: mechanisms and advances in clinical trials

et al. 2019

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Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, which can be considered as a master regulator for cancer. Enormous efforts have been dedicated to the development of drugs targeting PI3K signaling, many of which are currently employed in clinical trials evaluation, and it is becoming increasingly clear that PI3K inhibitors are effective in inhibiting tumor progression. PI3K inhibitors are subdivided into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors and isoform-specific inhibitors. In this review, we performed a critical review to summarize the role of the PI3K pathway in tumor development, recent PI3K inhibitors development based on clinical trials, and the mechanisms of resistance to PI3K inhibition.

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Section: Resistancesmentioning

confidence: 99%

Targeting PI3K in cancer: mechanisms and advances in clinical trials

et al. 2019

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“…A previous study focused on miR-135b, miR-182 and the PI3K/AKT signaling pathway in colorectal cancer (CRC), identifying that overexpressed miR-182 promotes the chemoresistance of CRC by targeting ST6 N-acetylgalactosaminide α-2,6-sialyltransferase 2 via the PI3K/AKT signaling pathway (42). Furthermore, the ability of miR-182 to activate the PI3K/AKT signaling pathway has previously been confirmed (31). These findings indicated that inhibition of miR-182 suppressed cell viability and invasion via the activation of CADM2 and by suppressing the PI3K/AKT signaling pathway.…”

Section: Discussionmentioning

confidence: 97%

“…Furthermore, another study identified that miR-182 overexpression is associated with VEGF-A production and angiogenesis (34). Liu et al (31) suggested that inhibition of miR-182 decreases the level of phosphorylated-AKT. MVD is used to measure angiogenesis, and it has been reported that enhanced angiogenesis appears in miR-182-overexpressing cells (36,37).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of microRNA‑182 inhibits cell viability, invasion and angiogenesis in retinoblastoma through inhibition of the PI3K/AKT pathway and CADM2 upregulation

Huang

Nie

et al. 2018

Int J Oncol

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Retinoblastoma (RB) is a well-vascularized tumor dependent on angiogenesis. The present study aimed to explore whether microRNA (miR)-182 regulates cell viability, invasion and angiogenesis in RB via the phosphatidylinositol-3-OH kinase (PI3K)/protein kinase B (AKT) signaling pathway and by targeting cell adhesion molecule 2 (CADM2). The expression levels of miR-182 and CADM2 were initially detected in RB tissues from patients with RB who underwent ophthalmectomy, and normal retinal tissues collected from other trauma patients who underwent eye enucleation. To determine whether CADM2 was targeted by miR-182, a dual luciferase reporter assay was conducted. Subsequently, Y79 and WERI-Rb-1 RB cells were transfected with a miR-182 mimic or miR-182 inhibitor, or small interfering RNA against CADM2, in order to investigate the effects of miR-182 on viability and invasion, which were detected using MTT and Transwell assays, respectively. In addition, to determine whether the regulatory mechanism underlying the effects of miR-182 was associated with the PI3K/AKT signaling pathway, the expression levels of associated genes were detected by reverse transcription-quantitative polymerase chain reaction and western blot analysis. A xenograft tumor model in nude mice was also established, in order to evaluate the effects of miR-182 on tumor growth and angiogenesis. The results indicated that miR-182 expression was increased and CADM2 expression was reduced in RB tissues; CADM2 was confirmed to be targeted and negatively regulated by miR-182. When the expression of miR-182 was downregulated, cell viability, invasion, tumor volume and angiogenesis were significantly decreased. Furthermore, the expression levels of PI3K/AKT signaling pathway-associated genes were increased in response to miR-182 overexpression or CADM2 silencing. Taken together, these results suggested that inhibition of miR-182 may suppress cell viability, invasion and angiogenesis in RB through inactivation of the PI3K/AKT pathway and CADM2 upregulation. This mechanism may reveal a novel potential therapeutic target.

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“…It is clear that miR-135b is an important oncogenic effector in cancers. Moreover, some studies suggest that miR-135b acts as a contributor to anti-apoptosis and chemoresistance in CRC [40,41]. However, the potential mechanisms are required to be explored.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Mir-135b Sensitizes Colorectal Cancer Cells to Oxaliplatin-Induced Apoptosis Through Increase of FOXO1

Yan

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Aberrant expression of microRNAs (miRNAs) is found to be responsible for tumorigenesis, cancer development and chemoresistance. Although oxaliplatin is an effective chemotherapeutic drug for treatment of colorectal cancer (CRC), CRC cells can develop some mechanisms to evade oxaliplatin-induced cell death. It is urgent to explore the novel strategies to increase the chemosensitivity of CRC cells. Methods: QRT-PCR analysis was performed to detect the expression of miR-135b in CRC patients’ serum and CRC cell lines. MTT assays were used to evaluate the effect of anti-miR-135b on oxaliplatin-induced cell death in CRC cell lines. Western blot, flow cytometry and luciferase reporter assays were performed to evaluate the potential mechanism and pathway of anti-miR-135b-promoted apoptosis in oxaliplatin-treated CRC cells. Results: Significant upregulation of miR-135b was observed in CRC cell lines and CRC patients’ serum. Knockdown of miR-135b was found to sensitize colorectal cancer cells to oxaliplatin-induced cytotoxicity. Mechanically, knockdown of miR-135b increased the expression level of FOXO1 in CRC. As the downstream, the increased FOXO1 induced by anti-miR-135b promoted the expression of Bim and Noxa. Since Bim and Noxa act as key pro-apoptotic proteins in mitochondrial apoptosis, anti-miR-135b was able to enhance the oxaliplatin-induced apoptosis dependent on the anti-miR-135b/FOXO1 axis. Conclusions: Anti-miR-135b enhanced the anti-tumor effect of oxaliplatin on CRC. Combination with miR-135b antisense nucleotides may represent a novel strategy to sensitize CRC to oxaliplatin-based treatment.

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Upregulation of microRNA‐135b and microRNA‐182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3K/AKT pathway

Cited by 76 publications

References 38 publications

Targeting PI3K in cancer: mechanisms and advances in clinical trials

Targeting PI3K in cancer: mechanisms and advances in clinical trials

Downregulation of microRNA‑182 inhibits cell viability, invasion and angiogenesis in retinoblastoma through inhibition of the PI3K/AKT pathway and CADM2 upregulation

Knockdown of Mir-135b Sensitizes Colorectal Cancer Cells to Oxaliplatin-Induced Apoptosis Through Increase of FOXO1

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