Korean J Physiol Pharmacol.  2023 Jan;27(1):61-73. 10.4196/kjpp.2023.27.1.61.

Exosome-mediated lnc-ABCA12-3 promotes proliferation and glycolysis but inhibits apoptosis by regulating the tolllike receptor 4/nuclear factor kappa-B signaling pathway in esophageal squamous cell carcinoma

• Ma J
• Luo Y
• Liu Y
• Chen C
• Chen A
• Liang L
• Wang W
• Song Y

• KMID: 2537504
• DOI: http://doi.org/10.4196/kjpp.2023.27.1.61

Abstract

Esophageal squamous cell carcinoma (ESCC) is a kind of malignant tumor with high incidence and mortality in the digestive system. The aim of this study is to explore the function of lnc-ABCA12-3 in the development of ESCC and its unique mechanisms. RT-PCR was applied to detect gene transcription levels in tissues or cell lines like TE-1, EC9706, and HEEC cells. Western blot was conducted to identify protein expression levels of mitochondrial apoptosis and toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway. CCK-8 and EdU assays were carried out to measure cell proliferation, and cell apoptosis was examined by flow cytometry. ELISA was used for checking the changes in glycolysis-related indicators. Lnc-ABCA12-3 was highly expressed in ESCC tissues and cells, which preferred it to be a candidate target. The TE-1 and EC9706 cells proliferation and glycolysis were obviously inhibited with the downregulation of lnc-ABCA12-3, while apoptosis was promoted. TLR4 activator could largely reverse the apoptosis acceleration and relieved the proliferation and glycolysis suppression caused by lnc-ABCA12-3 downregulation. Moreover, the effect of lnc-ABCA12-3 on ESCC cells was actualized by activating the TLR4/NF-κB signaling pathway under the mediation of exosome. Taken together, the lnc-ABCA12-3 could promote the proliferation and glycolysis of ESCC, while repressing its apoptosis probably by regulating the TLR4/NF-κB signaling pathway under the mediation of exosome.

Keyword

Esophageal squamous cell carcinoma; Exosomes; Lnc-ABCA12-3; Toll-like receptor 4; NF-kappa B

Figure

• 

  Fig. 1 Lnc-ABCA12-3 was overexpressed in esophageal squamous cell carcinoma (ESCC) tissues, serum (exosomes), and cells. (A) Volcanic diagram of differential distribution of lncRNAs expression in microarray of ESCC and adjacent normal tissues. (B) The top 10 upregulation and downregulation of differentially expressed lncRNAs was showed in heat map. (C) Lnc-ABCA12-3 levels in normal and tumor tissues were measured by RT-PCR. **p < 0.01 vs. Normal tissues group. (D) Lnc-ABCA12-3 levels in serum from healthy people and ESCC patients were measured by RT-PCR. ##p < 0.01 vs. Control group. (E) Lnc-ABCA12-3 levels in serum-exosomes from healthy people and ESCC patients were detected by RT-PCR. &&p < 0.01 vs. Control group. (F) Lnc-ABCA12-3 levels in HEEC, TE-1, and EC9706 cells were assessed by RT-PCR. ^^p < 0.01 vs. HEEC group. Data were presented as mean ± SD.

• 

  Fig. 2 Knockdown of lnc-ABCA12-3 inhibited the proliferation and glycolysis of esophageal squamous cell carcinoma (ESCC) cells. (A) After transfection with sh-ABCA12-3, lnc-ABCA12-3 expression was measured by RT-PCR. (B) The viability of ESCC cells were assessed by CCK-8 assay. (C, D) The proliferation was detected by EdU assay. Scale bar, 20 μm. (E–G) The contents of ATP, glucose uptake, and lactic acid production were tested by the corresponding commercial kits. Data were presented as mean ± SD. **p < 0.01 vs. sh-NC group.

• 

  Fig. 3 Knockdown of lnc-ABCA12-3 promoted the apoptosis of esophageal squamous cell carcinoma (ESCC) cells. (A, B) ESCC cells apoptosis were measured by flow cytometry. (C, D) The expression of Bax, Bcl-2, caspase-3, cleaved caspase-3 were detected by Western blot. Data were presented as mean ± SD. **p < 0.01 vs. sh-NC group.

• 

  Fig. 4 Knockdown of lnc-ABCA12-3 inactivated toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway. (A, B) The expression of TLR4, IκBα, p-IκBα, NF-κB, p-NF-κB were assessed by Western blot. Data were presented as mean ± SD. **p < 0.01 vs. sh-NC group.

• 

  Fig. 5 Lnc-ABCA12-3 regulated proliferation, glycolysis and apoptosis via activating TLR4. (A) The viability of esophageal squamous cell carcinoma (ESCC) cells were assessed by CCK-8 assay. (B, C) The proliferation was detected by EdU assay. Scale bar, 20 μm. (D–F) The contents of ATP, glucose uptake, and lactic acid production were tested by the corresponding commercial kits. (G, H) ESCC cells apoptosis were measured by flow cytometry. Data were presented as mean ± SD. TLR4, toll-like receptor 4; LPS, lipopolysaccharide. **p < 0.01 vs. sh-NC group, ##p < 0.01 vs. sh-ABCA12-3 group.

• 

  Fig. 6 The effect of lnc-ABCA12-3 on mitochondrial apoptosis pathway and toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway in esophageal squamous cell carcinoma (ESCC) cells treated with LPS. (A) The expression of Bax, Bcl-2, caspase-3, cleaved caspase-3 were detected by Western blot. (B) The expression of TLR4, IκBα, p-IκBα, NF-κB, p-NF-κB were assessed by Western blot. Data were presented as mean ± SD. LPS, lipopolysaccharide. **p < 0.01 vs. sh-NC group, ##p < 0.01 vs. sh-ABCA12-3 group.

• 

  Fig. 7 Lnc-ABCA12-3 functioned with the esophageal squamous cell carcinoma (ESCC) cells was under the mediated of exosomes. (A) After treatment with exosomes from TE-1 cells transfected with or without sh-ABCA12-3. Lnc-ABCA12-3 expression was measured by RT-PCR. (B) The viability of ESCC cells were assessed by CCK-8 assay. (C, D) The proliferation was detected by EdU assay. Scale bar, 20 μm. (E–G) The contents of ATP, glucose uptake, and lactic acid production were tested by the corresponding commercial kits. Data were presented as mean ± SD. **p < 0.01 vs. control group, ##p < 0.01 vs. TE-1-exo group, &&p < 0.01 vs. sh-NC-TE-1-exo group.

• 

  Fig. 8 Lnc-ABCA12-3 regulated mitochondrial apoptosis pathway and toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway under the mediated of exosomes. (A) The expression of Bax, Bcl-2, caspase-3, cleaved caspase-3 were detected by Western blot. (B) The expression of TLR4, IκBα, p-IκBα, NF-κB, p-NF-κB were assessed by Western blot. Data were presented as mean ± SD. **p < 0.01 vs. control group, ##p < 0.01 vs. TE-1-exo group, &&p < 0.01 vs. sh-NC-TE-1-exo group.

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