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. 2018 May 15;37(1):104.
doi: 10.1186/s13046-018-0769-4.

Chibby suppresses aerobic glycolysis and proliferation of nasopharyngeal carcinoma via the Wnt/β-catenin-Lin28/let7-PDK1 cascade

Cheng-Fu Cai  1   2   3 , Guo-Dong Ye  4   5 , Dong-Yan Shen  3 , Wei Zhang  3 , Mao-Li Chen  6   7 , Xin-Xin Chen  6   7 , Da-Xiong Han  7 , Yan-Jun Mi  3 , Qi-Cong Luo  3 , Wang-Yu Cai  3 , Shu-Yu Yang  8   9
Affiliations

Chibby suppresses aerobic glycolysis and proliferation of nasopharyngeal carcinoma via the Wnt/β-catenin-Lin28/let7-PDK1 cascade

Cheng-Fu Cai et al. J Exp Clin Cancer Res. .

Abstract

Background: Great progress has been achieved in the study of the aerobic glycolysis or the so-called Warburg effect in a variety of cancers; however, the regulation of the Warburg effect in Nasopharyngeal carcinoma (NPC) has not been completely defined VSports手机版. .

Methods: Gene expression pattern of NPC cells were used to test associations between Chibby and β-catenin expression. Chibby siRNAs and over-expression vector were transfected into NPC cells to down-regulate or up-regulate Chibby expression. Loss- and gain-of function assays were performed to investigate the role of Chibby in NPC cells. Western blot, cell proliferation, Glucose uptake, Lactate release, ATP level, and O2 consumption assays were used to determine the mechanism of Chibby regulation of underlying targets V体育安卓版. Finally, immunohistochemistry assay of fresh NPC and nasopharyngeal normal tissue sample were used to detect the expression of Chibby, β-Catenin, and PDK1 by immunostaining. .

Results: We observed that Chibby, a β-catenin-associated antagonist, is down-regulated in nasopharyngeal carcinoma cell lines and inhibits Wnt/β-Catenin signaling induced Warburg effect. Mechanism study revealed that Chibby regulates aerobic glycolysis in NPC cells through pyruvate dehydrogenase kinase 1(PDK1), an important enzyme involved in glucose metabolism. Moreover, Chibby suppresses aerobic glycolysis of NPC via Wnt/β-Catenin-Lin28/let7-PDK1 cascade. Chibby and PDK1 are critical for Wnt/β-Catenin signaling induced NPC cell proliferation both in vitro and in vivo. Finally, immunostaining assay of tissue samples provides an important clinical relevance among Chibby, Wnt/β-Catenin signaling and PDK1 V体育ios版. .

Conclusions: Our study reveals an association between Chibby expression and cancer aerobic glycolysis, which highlights the importance of Wnt/β-catenin pathway in regulation of energy metabolism of NPC. These results indicate that Chibby and PDK1 are the potential target for NPC treatment VSports最新版本. .

Keywords: Chibby; Nasopharyngeal carcinoma; Warburg effect; Wnt/β-Catenin signaling. V体育平台登录.

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Conflict of interest statement (VSports)

Ethics approval and consent to participate

The study was approved by the ethical review board of the First Affiliated Hospital of Xiamen University (Xiamen, China).

Competing interests

The authors declare that they have no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Expression pattern of Chibby and its effects on cell proliferation in NPC cells. a Quantitative and semi-quantitative polymerase chain reaction analysis of Chibby in a variety of cell lines including normal and NPC cells. b Western blotting analysis of Chibby and β-catenin from cell lysates or nuclear extracts of NPC cell lines. c Overexpression of Chibby suppressed cell proliferation (n = 3) in SUNE-1 and CNE2 cells. d Knockdown of Chibby enhanced cell proliferation (n = 3) in CNE1 and HK-1 cells. Data were expressed as the mean ± SD. **, p < 0.01
Fig. 2
Fig. 2
The effects of Chibby overexpression or knockdown on Warburg effect in NPC cells. a Western blotting analysis of Chibby in overexpressed SUNE-1 and CNE2 cells. b Cellular glucose uptake, c Lactate release, d ATP levels, e O2 consumption rates were measured in Chibby-overexpressed SUNE-1 and CNE2 cells. f Western blotting analysis of Chibby in knocked down CNE1 and HK-1 cells. g Cellular glucose uptake, h Lactate release, i ATP levels, j O2 consumption rates were measured in Chibby-knockdown CNE1 and HK-1 cells. Data were expressed as the mean ± SD, n = 6 for each group. *, p < 0.05; **, p < 0.01
Fig. 3
Fig. 3
PDK1 mediates Chibby-regulated aerobic glycolysis. a Western blotting analysis of metabolic enzymes in Chibby-overexpressed SUNE-1 and CNE2 cells. b mRNA levels of PDK1 were determined by quantitative polymerase chain reaction in Chibby-overexpressed SUNE-1 and CNE2 cells. c protein levels of PDK1 were determined by western blot in Chibby-knockdown CNE1 and HK-1 cells. d Cellular glucose uptake and lactate release levels were measured in Chibby-overexpressed SUNE-1 and CNE2 cells after PDK1 overexpression. e Cellular glucose uptake and lactate release levels were measured in Chibby-knockdown CNE1 and HK-1 cells following knockdown of PDK1. Data were expressed as the mean ± SD, n = 3 for each group. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ns, not significant
Fig. 4
Fig. 4
PDK1 is positively regulated by Wnt/β-catenin signaling via Lin28/Let7. a Western blotting analysis of Lin28 and PDK1 in β-catenin-overexpressed CNE1 and HK-1 cells. b mRNA levels of Lin28, let-7 g, and PDK1 were determined by quantitative polymerase chain reaction in β-catenin-overexpressed CNE1 and HK-1 cells. c Western blotting analysis of Lin28 and PDK1 in β-catenin-overexpressed CNE1 and HK-1 cells after Lin28 knockdown or Let-7 g overexpression. d Western blotting analysis of Lin28 and PDK1 in β-catenin-knockdown SUNE-1 and CNE2 cells after Lin28 overexpression or Let-7 g antagomir treatment. Data were expressed as the mean ± SD, n = 3 for each group. *, p < 0.05; **, p < 0.01; ns, not significant
Fig. 5
Fig. 5
Chibby inhibits Wnt/β-catenin signaling-induced PDK1 expression and aerobic glycolysis in NPC cells. a Western blotting analysis of PDK1 in β-catenin-overexpressed CNE1 and HK-1 cells after Chibby overexpression. b Cellular glucose uptake and lactate release levels were measured in β-catenin-overexpressed CNE1 and HK-1 cells following knockdown of PDK1. c Cellular glucose uptake, d Lactate levels were measured in CNE1 and HK-1 cells following overexpression of β-catenin, Chibby, PDK1, alone or in combination. Data were expressed as the mean ± SD, n = 3 for each group. *, p < 0.05; **, p < 0.001
Fig. 6
Fig. 6
The effects of Chibby and PDK1 on Wnt/β-catenin signaling-induced NPC cell proliferation. a Knockdown of PDK1 diminished the promoting effect of β-catenin on cell proliferation in CNE1 cells. b Cell proliferation rates were measured in CNE1 cells following overexpression of β-catenin, Chibby, PDK1, alone or in combination. c, d Representative photograph and tumor growth curve of CNE1 xenografts in nude mice. 4 × 106 cells of CNE1 were injected subcutaneously into mice. Tumor growth was monitored regularly for 7 weeks, then the tumor volume was calculated every week. Data were expressed as the mean ± SD, n = 6 for each group. *, p < 0.05; **, p < 0.01
Fig. 7
Fig. 7
Clinical relevance of Chibby, Wnt/β-catenin signaling and PDK1. a Representative immunostaining of Chibby, β-catenin and PDK1 in normal and NPC tissue samples. Scale bar: 100 μm. b Relative frequency of the immunoreactive scores for Chibby, β-catenin and PDK1 staining on 45 NPC tissues and 45 normal nasopharyngeal tissues. Fisher’s exact test was used for categorical variables (p < 0.001). c The correlation between Chibby and β-catenin protein levels. d The correlation between Chibby and PDK1 protein levels. e The correlation between β-catenin and PDK1 protein levels. Pearson’s correlation test was used for c to e (r and p values are shown in the graphs of c to e)
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