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HIV-1 Nef and KSHV oncogene K1 synergistically promote angiogenesis by inducing cellular miR-718 to regulate the PTEN/AKT/mTOR signaling pathway.

Xue M, Yao S, Hu M, Li W, Hao T, Zhou F, Zhu X, Lu H, Qin D, Yan Q, Zhu J, Gao SJ, Lu C - Nucleic Acids Res. (2014)

Bottom Line: Kaposi's sarcoma (KS) is an AIDS-defining cancer with aberrant neovascularization caused by KS-associated herpesvirus (KSHV).Furthermore, Nef and K1 induced cellular miR-718, which inhibited PTEN expression by directly targeting a seed sequence in the 3' UTR of its mRNA.Our results demonstrate an essential role of miR-718/AKT/mTOR axis in AIDS-KS and thus may represent an attractive therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P.R. China Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, P.R. China Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China Department of Physiology, Xuzhou Medical College, Xuzhou, Jiangsu 221004, P.R. China.

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miR-718 mediates K1- and Nef-induced tumorigenesis in nude mice. (A) Inhibition of miR-718 abrogates the enhanced effect of Nef on K1-induced tumorigenesis. EA.hy926 cells transduced with K1, Nef or both were infected with control virus (pCDH) or miR-718 sponge for 72 h and further re-suspended in serum-free medium. As detailed in the ‘Materials and Methods’ section, the treated cells were injected (s.c.) into nude mice. The sizes of tumors from nude mice were determined by two-dimensional caliper measurements. Data represent mean ± SD, each group with five tumors (n = 5). Two independent experiments were performed and similar results were obtained. ** and *** indicate P < 0.01 and P < 0.001 by Student's t-test, respectively. (B) Tumor-bearing mice were killed at day 56 after injections, and tumors were removed and pictures were taken. (C) Inhibition of miR-718 abrogates the enhanced effect of Nef on K1-induced tumorigenesis. The tumors from nude mice treated as in (A) were removed and weighed. Scatter plots represent the weights of independent tumors from different groups. Data represent mean ± SD, each group with five tumors (n = 5). Two independent experiments were performed and similar results were obtained. (D) Inhibition of miR-718 increased total PTEN level and suppressed the enhanced phosphorylation of AKT and mTOR by K1 and Nef. The tumor tissues from nude mice treated as in (A) were removed, and the expression of total PTEN, phosphorylation levels of AKT and mTOR in tumor tissues were analyzed by Western blot. Numbers labeled under the bands were the relative intensities of the bands after calibration for loading with the house-keeping protein tubulin. The relative value of proteins in K1 + pCDH group was considered as ‘1’.
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Figure 8: miR-718 mediates K1- and Nef-induced tumorigenesis in nude mice. (A) Inhibition of miR-718 abrogates the enhanced effect of Nef on K1-induced tumorigenesis. EA.hy926 cells transduced with K1, Nef or both were infected with control virus (pCDH) or miR-718 sponge for 72 h and further re-suspended in serum-free medium. As detailed in the ‘Materials and Methods’ section, the treated cells were injected (s.c.) into nude mice. The sizes of tumors from nude mice were determined by two-dimensional caliper measurements. Data represent mean ± SD, each group with five tumors (n = 5). Two independent experiments were performed and similar results were obtained. ** and *** indicate P < 0.01 and P < 0.001 by Student's t-test, respectively. (B) Tumor-bearing mice were killed at day 56 after injections, and tumors were removed and pictures were taken. (C) Inhibition of miR-718 abrogates the enhanced effect of Nef on K1-induced tumorigenesis. The tumors from nude mice treated as in (A) were removed and weighed. Scatter plots represent the weights of independent tumors from different groups. Data represent mean ± SD, each group with five tumors (n = 5). Two independent experiments were performed and similar results were obtained. (D) Inhibition of miR-718 increased total PTEN level and suppressed the enhanced phosphorylation of AKT and mTOR by K1 and Nef. The tumor tissues from nude mice treated as in (A) were removed, and the expression of total PTEN, phosphorylation levels of AKT and mTOR in tumor tissues were analyzed by Western blot. Numbers labeled under the bands were the relative intensities of the bands after calibration for loading with the house-keeping protein tubulin. The relative value of proteins in K1 + pCDH group was considered as ‘1’.

Mentions: To examine the role of miR-718 in Nef- and K1-induced tumorigenesis in nude mice, K1- or Nef-expressing, or K1 and Nef co-expressing EA.hy926 cells were infected with the lentiviral miR-718 sponge and then s.c. injected into nude mice. As shown in Figure 8A–C, miR-718 sponge effectively repressed the growth of tumors induced by Nef, K1 or both. Western blot analysis showed that the expression of miR-718 sponge not only led to elevation of PTEN, but also decreased phosphorylated forms of AKT and mTOR in all tumors (Figure 8D).


HIV-1 Nef and KSHV oncogene K1 synergistically promote angiogenesis by inducing cellular miR-718 to regulate the PTEN/AKT/mTOR signaling pathway.

Xue M, Yao S, Hu M, Li W, Hao T, Zhou F, Zhu X, Lu H, Qin D, Yan Q, Zhu J, Gao SJ, Lu C - Nucleic Acids Res. (2014)

miR-718 mediates K1- and Nef-induced tumorigenesis in nude mice. (A) Inhibition of miR-718 abrogates the enhanced effect of Nef on K1-induced tumorigenesis. EA.hy926 cells transduced with K1, Nef or both were infected with control virus (pCDH) or miR-718 sponge for 72 h and further re-suspended in serum-free medium. As detailed in the ‘Materials and Methods’ section, the treated cells were injected (s.c.) into nude mice. The sizes of tumors from nude mice were determined by two-dimensional caliper measurements. Data represent mean ± SD, each group with five tumors (n = 5). Two independent experiments were performed and similar results were obtained. ** and *** indicate P < 0.01 and P < 0.001 by Student's t-test, respectively. (B) Tumor-bearing mice were killed at day 56 after injections, and tumors were removed and pictures were taken. (C) Inhibition of miR-718 abrogates the enhanced effect of Nef on K1-induced tumorigenesis. The tumors from nude mice treated as in (A) were removed and weighed. Scatter plots represent the weights of independent tumors from different groups. Data represent mean ± SD, each group with five tumors (n = 5). Two independent experiments were performed and similar results were obtained. (D) Inhibition of miR-718 increased total PTEN level and suppressed the enhanced phosphorylation of AKT and mTOR by K1 and Nef. The tumor tissues from nude mice treated as in (A) were removed, and the expression of total PTEN, phosphorylation levels of AKT and mTOR in tumor tissues were analyzed by Western blot. Numbers labeled under the bands were the relative intensities of the bands after calibration for loading with the house-keeping protein tubulin. The relative value of proteins in K1 + pCDH group was considered as ‘1’.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 8: miR-718 mediates K1- and Nef-induced tumorigenesis in nude mice. (A) Inhibition of miR-718 abrogates the enhanced effect of Nef on K1-induced tumorigenesis. EA.hy926 cells transduced with K1, Nef or both were infected with control virus (pCDH) or miR-718 sponge for 72 h and further re-suspended in serum-free medium. As detailed in the ‘Materials and Methods’ section, the treated cells were injected (s.c.) into nude mice. The sizes of tumors from nude mice were determined by two-dimensional caliper measurements. Data represent mean ± SD, each group with five tumors (n = 5). Two independent experiments were performed and similar results were obtained. ** and *** indicate P < 0.01 and P < 0.001 by Student's t-test, respectively. (B) Tumor-bearing mice were killed at day 56 after injections, and tumors were removed and pictures were taken. (C) Inhibition of miR-718 abrogates the enhanced effect of Nef on K1-induced tumorigenesis. The tumors from nude mice treated as in (A) were removed and weighed. Scatter plots represent the weights of independent tumors from different groups. Data represent mean ± SD, each group with five tumors (n = 5). Two independent experiments were performed and similar results were obtained. (D) Inhibition of miR-718 increased total PTEN level and suppressed the enhanced phosphorylation of AKT and mTOR by K1 and Nef. The tumor tissues from nude mice treated as in (A) were removed, and the expression of total PTEN, phosphorylation levels of AKT and mTOR in tumor tissues were analyzed by Western blot. Numbers labeled under the bands were the relative intensities of the bands after calibration for loading with the house-keeping protein tubulin. The relative value of proteins in K1 + pCDH group was considered as ‘1’.
Mentions: To examine the role of miR-718 in Nef- and K1-induced tumorigenesis in nude mice, K1- or Nef-expressing, or K1 and Nef co-expressing EA.hy926 cells were infected with the lentiviral miR-718 sponge and then s.c. injected into nude mice. As shown in Figure 8A–C, miR-718 sponge effectively repressed the growth of tumors induced by Nef, K1 or both. Western blot analysis showed that the expression of miR-718 sponge not only led to elevation of PTEN, but also decreased phosphorylated forms of AKT and mTOR in all tumors (Figure 8D).

Bottom Line: Kaposi's sarcoma (KS) is an AIDS-defining cancer with aberrant neovascularization caused by KS-associated herpesvirus (KSHV).Furthermore, Nef and K1 induced cellular miR-718, which inhibited PTEN expression by directly targeting a seed sequence in the 3' UTR of its mRNA.Our results demonstrate an essential role of miR-718/AKT/mTOR axis in AIDS-KS and thus may represent an attractive therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P.R. China Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, P.R. China Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China Department of Physiology, Xuzhou Medical College, Xuzhou, Jiangsu 221004, P.R. China.

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Related in: MedlinePlus