MiR-145 negatively regulates Warburg effect by silencing KLF4 and PTBP1 in bladder cancer cells

Minami, Koichiro; Taniguchi, Kohei; Sugito, Nobuhiko; Kuranaga, Yuki; Inamoto, Teruo; Takahara, Kiyoshi; Takai, Tomoaki; Yoshikawa, Yuki; Kiyama, Satoshi; Akao, Yukihiro; Azuma, Haruhito

doi:10.18632/oncotarget.16524

Cited by 58 publications

(98 citation statements)

References 49 publications

(70 reference statements)

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“…Gefitinib can induce apoptosis by activating the caspase cascade in NSCLC cells carrying the sensitive mutation of EGFR . Krüppel‐like factor 4 also has an ambiguous apoptosis‐induced effect in bladder cancer cells, breast cancer cells, and plasma cells . The present study revealed that knockdown of KLF4 promoted gefitinib‐induced apoptosis by upregulating expression of apoptosis‐related proteins in c‐Met‐overexpressing NSCLC cells (Figure A,C) but not in NSCLC cells without c‐Met overexpression (Figure ), whereas overexpression of KLF4 suppressed gefitinib‐induced apoptosis in gefitinib‐sensitive cells (Figure B,D).…”

Section: Discussionmentioning

confidence: 48%

Krüppel‐like factor 4 promotes c‐Met amplification‐mediated gefitinib resistance in non‐small‐cell lung cancer

et al. 2018

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Gefitinib has been widely used in the first‐line treatment of advanced EGFR‐mutated non‐small‐cell lung cancer (NSCLC). However, many NSCLC patients will acquire resistance to gefitinib after 9‐14 months of treatment. This study revealed that Krüppel‐like factor 4 (KLF4) contributes to the formation of gefitinib resistance in c‐Met‐overexpressing NSCLC cells. We observed that KLF4 was overexpressed in c‐Met‐overexpressing NSCLC cells and tissues. Knockdown of KLF4 increased tumorigenic properties in gefitinib‐resistant NSCLC cell lines without c‐Met overexpression, but it reduced tumorigenic properties and increased gefitinib sensitivity in gefitinib‐resistant NSCLC cells with c‐Met overexpression, whereas overexpression of KLF4 reduced gefitinib sensitivity in gefitinib‐sensitive NSCLC cells. Furthermore, Western blot analysis revealed that KLF4 contributed to the formation of gefitinib resistance in c‐Met‐overexpressing NSCLC cells by inhibiting the expression of apoptosis‐related proteins under gefitinib treatment and activating the c‐Met/Akt signaling pathway by decreasing the inhibition of β‐catenin on phosphorylation of c‐Met to prevent blockade by gefitinib. In summary, this study's results suggest that KLF4 is a promising candidate molecular target for both prevention and therapy of NSCLC with c‐Met overexpression.

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Section: Discussionmentioning

confidence: 48%

Krüppel‐like factor 4 promotes c‐Met amplification‐mediated gefitinib resistance in non‐small‐cell lung cancer

et al. 2018

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“…34 Recent studies have shown that miR-145 perturbed the Warburg effect by suppressing the pathway of KLF4/PTBP1/PKM in bladder cancer cells. 35 The downstream mechanisms of miR-145 that alter cellular processes have been partially confirmed in several published studies. In comparison, the upstream mechanism by which miR-145 is downregulated in EOC remains less well understood.…”

Section: Expression Of Hk2 and Dnmt3a In Ovarian Cancer Tissue Subcmentioning

confidence: 80%

“…In liver cancer cells, miR‐145 abolished insulin‐induced PKM2 expression; however, the interaction between miR‐145 and PKM2 was not determined . Recent studies have shown that miR‐145 perturbed the Warburg effect by suppressing the pathway of KLF4/PTBP1/PKM in bladder cancer cells …”

Section: Discussionmentioning

confidence: 99%

Double‐negative feedback interaction between DNA methyltransferase 3A and microRNA‐145 in the Warburg effect of ovarian cancer cells

Zhang

Pei

et al. 2018

Cancer Science

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Ovarian cancer is the most lethal gynecological malignancy because of its poor prognosis. The Warburg effect is one of the key mechanisms mediating cancer progression. Molecules targeting the Warburg effect are therefore of significant therapeutic value for the treatment of cancers. Many microRNAs (miR) are dysregulated in cancers, and aberrant miR expression patterns have been suggested to correlate with the Warburg effect in cancer cells. In our study, we found that miR‐145 negatively correlated with DNA methyltransferase (DNMT)3A expression at cellular/histological levels. miR‐145 inhibited the Warburg effect by targeting HK2. Luciferase reporter assays confirmed that miR‐145‐mediated downregulation of DNMT3A occurred through direct targeting of its mRNA 3′‐UTRs, whereas methylation‐specific PCR (MSP) assays found that knockdown of DNMT3A increased mRNA level of miR‐145 and decreased methylation levels of promoter regions in the miR‐145 precursor gene, thus suggesting a crucial crosstalk between miR‐145 and DNMT3A by a double‐negative feedback loop. DNMT3A promoted the Warburg effect through miR‐145. Coimmunoprecipitation assays confirmed no direct binding between DNMT3A and HK2. In conclusion, a feedback loop between miR‐145 and DNMT3A is a potent signature for the Warburg effect in ovarian cancer, promising a potential target for improved anticancer treatment.

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“…miR-145 inhibits the Warburg effect by inhibiting KLF4 and PTBP1 in bladder cancer (Iorio et al, 2005;Minami et al, 2017). miR-145 has also been found to cluster with miR-143 to regulate HK2 in renal cell carcinoma (Takai et al, 2017;Yoshino et al, 2013).…”

Section: Discussionmentioning

confidence: 97%

“…Research has focused on cell proliferation and migration (Arndt et al, ; Iorio et al, ); reports related to aerobic glycolysis are rare. miR‐145 inhibits the Warburg effect by inhibiting KLF4 and PTBP1 in bladder cancer (Iorio et al, ; Minami et al, ). miR‐145 has also been found to cluster with miR‐143 to regulate HK2 in renal cell carcinoma (Takai et al, ; Yoshino et al, ).…”

Section: Discussionmentioning

confidence: 99%

miR‐145 promotes miR‐133b expression through c‐myc and DNMT3A‐mediated methylation in ovarian cancer cells

Zhang

Zou

et al. 2019

Journal Cellular Physiology

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Ovarian cancer presents as malignant tumors in the female reproductive system with high mortality. MicroRNAs are involved in the progression of ovarian cancer; however, the regulatory relationship among miRs remains unclear. In our study, we verified that both miR-145 and miR-133b messenger RNA (mRNA) levels in ovarian cancer tissues were lower than in normal ovarian tissues, and their mRNA level in serum of patients with ovarian cancer was reduced. We demonstrated miR-145 targeted c-myc, and c-myc interacted physically with DNMT3A in ovarian cancer cells. We confirmed that c-myc recruited DNMT3A to the miR-133b promoter. miR-133b overexpression also inhibited target gene PKM2 expression along with the Warburg effect. Our results indicate that miR-145 inhibited the Warburg effect through miR-133b/PKM2 pathways, which may improve approaches to ovarian cancer diagnosis and treatment. K E Y W O R D Sc-myc, DNMT3A, miR-133b, miR-145, ovarian cancer, Warburg effect

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MiR-145 negatively regulates Warburg effect by silencing KLF4 and PTBP1 in bladder cancer cells

Cited by 58 publications

References 49 publications

Krüppel‐like factor 4 promotes c‐Met amplification‐mediated gefitinib resistance in non‐small‐cell lung cancer

Krüppel‐like factor 4 promotes c‐Met amplification‐mediated gefitinib resistance in non‐small‐cell lung cancer

Double‐negative feedback interaction between DNA methyltransferase 3A and microRNA‐145 in the Warburg effect of ovarian cancer cells

miR‐145 promotes miR‐133b expression through c‐myc and DNMT3A‐mediated methylation in ovarian cancer cells

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