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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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Nef promotes K1 induction of tumors in nude mice. (A) A Kaplan–Meier plot for the time until the appearance of palpable tumors. EA.hy926 cells transduced by K1, Nef or both were s.c. injected into the left flanks of nude mice. The palpable tumor appearances of mice were daily monitored for 60 days. (B) Nef enhanced K1-induced tumorigenesis indicated by tumor size. The sizes of tumors from nude mice that treated as in (A) were determined by two-dimensional caliper measurements. Data represent mean ± SD. n = 5 tumors per group. Two independent experiments were performed and gave similar results. ** and *** indicate P < 0.01 and P < 0.001 for Student's t-test, respectively. (C) Nef enhanced K1-induced tumorigenesis indicated by tumor weight. The tumors from nude mice that treated as in (A) were removed and weighed. Scatter plots represent the weight 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) H&E staining analysis of histological features (top; original magnification, ×100) and immunohistochemical staining analysis of the expression of SMA and VEGF (middle and bottom; original magnification, ×200) in tumor tissues from nude mice treated as in (A). Black arrows point to neovascularization and hemorrhagic foci. (E) Quantification of results in (D).
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Figure 4: Nef promotes K1 induction of tumors in nude mice. (A) A Kaplan–Meier plot for the time until the appearance of palpable tumors. EA.hy926 cells transduced by K1, Nef or both were s.c. injected into the left flanks of nude mice. The palpable tumor appearances of mice were daily monitored for 60 days. (B) Nef enhanced K1-induced tumorigenesis indicated by tumor size. The sizes of tumors from nude mice that treated as in (A) were determined by two-dimensional caliper measurements. Data represent mean ± SD. n = 5 tumors per group. Two independent experiments were performed and gave similar results. ** and *** indicate P < 0.01 and P < 0.001 for Student's t-test, respectively. (C) Nef enhanced K1-induced tumorigenesis indicated by tumor weight. The tumors from nude mice that treated as in (A) were removed and weighed. Scatter plots represent the weight 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) H&E staining analysis of histological features (top; original magnification, ×100) and immunohistochemical staining analysis of the expression of SMA and VEGF (middle and bottom; original magnification, ×200) in tumor tissues from nude mice treated as in (A). Black arrows point to neovascularization and hemorrhagic foci. (E) Quantification of results in (D).

Mentions: We next investigated the effect of Nef and K1 on the growth of tumors in nude mice. Tumors of EA.hy926 cells expressing either Nef or K1 alone grew faster and had a shorter latency than the control group (Mock) had (Figure 4A–C). Co-expression of Nef and K1 further promoted tumor growth with the fastest growth rate and the shortest tumor latency (Figure 4A–C). H&E staining of the tumors showed extensive dense neovascularization and hemorrhagic necrotic foci in K1- or Nef-induced tumors, which became even more prominent in the tumors induced by both K1 and Nef (Figure 4D). Immunohistochemical staining of tumors indicated that there were more SMA- and VEGF-positive cells in tumors induced by K1 or Nef, which were further increased in tumors induced by both K1 and Nef (Figure 4D and E).


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)

Nef promotes K1 induction of tumors in nude mice. (A) A Kaplan–Meier plot for the time until the appearance of palpable tumors. EA.hy926 cells transduced by K1, Nef or both were s.c. injected into the left flanks of nude mice. The palpable tumor appearances of mice were daily monitored for 60 days. (B) Nef enhanced K1-induced tumorigenesis indicated by tumor size. The sizes of tumors from nude mice that treated as in (A) were determined by two-dimensional caliper measurements. Data represent mean ± SD. n = 5 tumors per group. Two independent experiments were performed and gave similar results. ** and *** indicate P < 0.01 and P < 0.001 for Student's t-test, respectively. (C) Nef enhanced K1-induced tumorigenesis indicated by tumor weight. The tumors from nude mice that treated as in (A) were removed and weighed. Scatter plots represent the weight 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) H&E staining analysis of histological features (top; original magnification, ×100) and immunohistochemical staining analysis of the expression of SMA and VEGF (middle and bottom; original magnification, ×200) in tumor tissues from nude mice treated as in (A). Black arrows point to neovascularization and hemorrhagic foci. (E) Quantification of results in (D).
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Related In: Results  -  Collection

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Figure 4: Nef promotes K1 induction of tumors in nude mice. (A) A Kaplan–Meier plot for the time until the appearance of palpable tumors. EA.hy926 cells transduced by K1, Nef or both were s.c. injected into the left flanks of nude mice. The palpable tumor appearances of mice were daily monitored for 60 days. (B) Nef enhanced K1-induced tumorigenesis indicated by tumor size. The sizes of tumors from nude mice that treated as in (A) were determined by two-dimensional caliper measurements. Data represent mean ± SD. n = 5 tumors per group. Two independent experiments were performed and gave similar results. ** and *** indicate P < 0.01 and P < 0.001 for Student's t-test, respectively. (C) Nef enhanced K1-induced tumorigenesis indicated by tumor weight. The tumors from nude mice that treated as in (A) were removed and weighed. Scatter plots represent the weight 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) H&E staining analysis of histological features (top; original magnification, ×100) and immunohistochemical staining analysis of the expression of SMA and VEGF (middle and bottom; original magnification, ×200) in tumor tissues from nude mice treated as in (A). Black arrows point to neovascularization and hemorrhagic foci. (E) Quantification of results in (D).
Mentions: We next investigated the effect of Nef and K1 on the growth of tumors in nude mice. Tumors of EA.hy926 cells expressing either Nef or K1 alone grew faster and had a shorter latency than the control group (Mock) had (Figure 4A–C). Co-expression of Nef and K1 further promoted tumor growth with the fastest growth rate and the shortest tumor latency (Figure 4A–C). H&E staining of the tumors showed extensive dense neovascularization and hemorrhagic necrotic foci in K1- or Nef-induced tumors, which became even more prominent in the tumors induced by both K1 and Nef (Figure 4D). Immunohistochemical staining of tumors indicated that there were more SMA- and VEGF-positive cells in tumors induced by K1 or Nef, which were further increased in tumors induced by both K1 and Nef (Figure 4D and E).

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