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PTEN Is a Major Tumor Suppressor in Pancreatic Ductal Adenocarcinoma and Regulates an NF-κB–Cytokine Network

Haoqiang Ying, Kutlu G. Elpek, Anant Vinjamoori, Stephanie M. Zimmerman, Gerald C. Chu, Haiyan Yan, Eliot Fletcher-Sananikone, Hailei Zhang, Yingchun Liu, Wei Wang, Xiaojia Ren, Hongwu Zheng, Alec C. Kimmelman, Ji-hye Paik, Carol Lim, Samuel R. Perry, Shan Jiang, Brian Malinn, Alexei Protopopov, Simona Colla, Yonghong Xiao, Aram F. Hezel, Nabeel Bardeesy, Shannon J. Turley, Y. Alan Wang, Lynda Chin, Sarah P. Thayer and Ronald A. DePinho
Haoqiang Ying
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Kutlu G. Elpek
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Anant Vinjamoori
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Stephanie M. Zimmerman
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Gerald C. Chu
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Haiyan Yan
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Eliot Fletcher-Sananikone
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Hailei Zhang
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Yingchun Liu
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Wei Wang
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Xiaojia Ren
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Hongwu Zheng
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Alec C. Kimmelman
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Ji-hye Paik
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Carol Lim
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Samuel R. Perry
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Shan Jiang
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Brian Malinn
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Alexei Protopopov
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Simona Colla
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Yonghong Xiao
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Aram F. Hezel
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Nabeel Bardeesy
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Shannon J. Turley
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Y. Alan Wang
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Lynda Chin
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Sarah P. Thayer
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Ronald A. DePinho
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DOI: 10.1158/2159-8290.CD-11-0031 Published July 2011
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    Figure 1.

    PTEN is deleted/downregulated in human pancreatic cancer, and Pten inactivation cooperates with KrasG12D to induce PDAC. A, representative IHC images of PTEN and pAKT staining from the TMA analysis showing samples with low or no PTEN staining and moderate to high pAKT (i, ii) or high PTEN staining and low pAKT (iii). Statistical analysis of the TMA data is shown in the bottom panel. pAKT, phospho-AKT. B, aCGH heat map detailing patterns of PTEN deletion and AKT2 gain/amplification in primary PDAC tumor specimens. Regions of amplification and deletion are denoted in red and blue, respectively. The arrowhead indicates the sample with concomitant PTEN deletion and AKT2 amplification. C, Kaplan–Meier overall survival analysis for mice of indicated genotypes. Cohort size for each genotype is indicated. D, typical ductal adenocarcinoma observed in a Pdx1-Cre LSL-KrasG12D PtenL/+ animal showing well-differentiated glandular tumor cells (i) that are positive for the ductal marker, cytokeratin-19 (ii), and are negative for the acinar marker, amylase (iii), and the endocrine marker, insulin (iv). CK19, cytokeratin-19. Scale bars, 100 μm.

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    Figure 2.

    Pten deficiency induces strong stromal reaction with immune cell infiltration and promotes the development of invasive and metastatic pancreatic tumors in cooperation with KrasG12D. A, six-week-old pancreata from KrasG12D (i–v) and KrasG12D PtenL/+ (vi–x) stained with H&E (i, vi), or with antibodies to SMA (ii, vii), S100A4 (iii, viii), Gr-1 (iv, ix), and FoxP3 (v, x). B, left, analysis of myeloid cells. Bar graph showing percentage of CD45+CD11b+Gr-1low (white) and Gr-1high (black) cells in total live cells of wild-type (n = 3), KrasG12D (n = 3), and KrasG12D PtenL/+ (n = 3) pancreata. Right, Treg analysis. Percentage of CD25+FoxP3+ cells within CD4+ T cells in pancreas of wild-type (n = 2), KrasG12D (n = 2) and KrasG12D PtenL/+ (n = 2) mice. *, P < 0.05; **, P < 0.01. C, tumor invasion and metastases. Gross picture shows liver metastases (i). H&E staining shows local invasion into duodenum wall (ii), lymph node metastasis (iii), liver metastasis (iv), and microscopic lung metastasis (vi). Liver metastasis is stained with cytokeratin-19 antibody (v). Scale bars, 100 μm.

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    Figure 3.

    Molecular analysis of KrasG12D PtenL/+ PDACs. A, PCR analysis of the Pten locus in genomic DNA from primary murine PDAC cell lines (lanes 2, 4, 6, 8, and 10) and control tail DNA from the same animal (lanes 1, 3, 5, 7, and 9). Although all control tail DNA showed both wild-type (Pten+) and Pten lox (PtenL) alleles (lanes 1, 3, 5, 7, and 9), and deleted Pten (PtenD) allele was present in all tumor DNA (lanes 2, 4, 6, 8, and 10), 3 tumor lines maintain the wild-type Pten allele (lanes 4, 6, and 8). B, Pten IHC staining in tumors with Pten LOH (top) or wild-type Pten allele (bottom) Scale bar, 100 μm. C, Western blot analysis for p16Ink4a, p19Arf, and Smad4 expression in early-passage KrasG12D (lanes 1–3) or KrasG12D PtenL/+ (lanes 4–7) PDEC lines and KrasG12D PtenL/+ PDAC lines (lanes 8–12). PDAC line from KrasG12D p53L/+ was used as a control (lane 13). D, KrasG12D PtenL/+ PDAC cell lines were treated with doxorubicin 0.4 μg/mL for 16 hours and collected for Western blot analysis for p53 and p21. KrasG12D p53L/+ tumor line was used as a negative control (lanes 11 and 12).

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    Figure 4.

    Pten deficiency activates the NF-κB pathway. A, cytoplasmic (C) or nuclear (N) extract was prepared from KrasG12D (lanes 1–4) or KrasG12D PtenL/+ (lanes 5–12) PDECs and blotted for NF-κB p65. Lamin A/C and caspase 3 were used as markers for nuclear and cytoplasmic fraction, respectively. KrasG12D PtenL/+ PDECs were also treated with either vehicle (Ctr) or LY, 20 μM, for 24 hours before collection. B, KrasG12D or KrasG12D PtenL/+ PDECs were transfected with NF-κB–luciferase reporter, and KrasG12D PtenL/+ PDECs were treated with either vehicle (Ctr) or LY, 20 μM, for 24 hours before being collected for luciferase activity assay. *, P < 0.05; **, P < 0.01. C, six-week-old pancreata from KrasG12D (top) and KrasG12D PtenL/+ (bottom) mice were stained with phospho–NF-κB p65 (pRelA) Scale bars, 100 μm. D. KrasG12D PDECs were infected with pSuper (Ctr) or pSuper-shPten (shPten) and blotted for Pten, pAkt, and Akt (lanes 1–4). Cytoplasmic (C) or nuclear (N) extract was blotted for NF-κB p65 (lanes 5–12).

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    Figure 5.

    Suppression of NF-κB inhibits tumorigenic activity. A, PDAC from KrasG12D PtenL/+ animals was stained for phospho–NF-κB p65 (pRelA) Scale bar, 100 μm. B, colony formation assay for KrasG12D PtenL/+ PDAC cell lines infected with pBabe (Vec) or pBabe-IκBαM. Quantification of colony numbers was shown on the right. C, KrasG12D PtenL/+ PDAC cell lines were infected with pBabe (Vec) or pBabe-IκBαM and injected s.c. into nude mice with Vec in the left flank and IκBαM in the right flank, respectively. Tumor volumes were measured in D. *, P < 0.05; **, P < 0.01.

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    Figure 6.

    Pten deficiency induces cytokine expression. A, expression of indicated cytokines and chemokines was measured by quantitative PCR (qPCR) in KrasG12D (n = 3) or KrasG12D PtenL/+ (n = 5) PDECs. B, expression of indicated cytokines and chemokines was measured by qPCR in KrasG12D PtenL/+ PDECs infected with pBabe (Vec) or pBabe-IκBαM. C, expression of indicated cytokines and chemokines was measured by qPCR in KrasG12D PtenL/+ PDECs treated with vehicle (Ctr) or LY-LY, 20 μM, for 24 hours. D, expression of indicated cytokines and chemokines was measured by qPCR in KrasG12D PDECs infected with pSuper (Ctr) or pSuper-shPten (shPten). *, P < 0.05; **, P < 0.01.

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Cancer Discovery: 1 (2)
July 2011
Volume 1, Issue 2
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PTEN Is a Major Tumor Suppressor in Pancreatic Ductal Adenocarcinoma and Regulates an NF-κB–Cytokine Network
Haoqiang Ying, Kutlu G. Elpek, Anant Vinjamoori, Stephanie M. Zimmerman, Gerald C. Chu, Haiyan Yan, Eliot Fletcher-Sananikone, Hailei Zhang, Yingchun Liu, Wei Wang, Xiaojia Ren, Hongwu Zheng, Alec C. Kimmelman, Ji-hye Paik, Carol Lim, Samuel R. Perry, Shan Jiang, Brian Malinn, Alexei Protopopov, Simona Colla, Yonghong Xiao, Aram F. Hezel, Nabeel Bardeesy, Shannon J. Turley, Y. Alan Wang, Lynda Chin, Sarah P. Thayer and Ronald A. DePinho
Cancer Discov July 1 2011 (1) (2) 158-169; DOI: 10.1158/2159-8290.CD-11-0031

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PTEN Is a Major Tumor Suppressor in Pancreatic Ductal Adenocarcinoma and Regulates an NF-κB–Cytokine Network
Haoqiang Ying, Kutlu G. Elpek, Anant Vinjamoori, Stephanie M. Zimmerman, Gerald C. Chu, Haiyan Yan, Eliot Fletcher-Sananikone, Hailei Zhang, Yingchun Liu, Wei Wang, Xiaojia Ren, Hongwu Zheng, Alec C. Kimmelman, Ji-hye Paik, Carol Lim, Samuel R. Perry, Shan Jiang, Brian Malinn, Alexei Protopopov, Simona Colla, Yonghong Xiao, Aram F. Hezel, Nabeel Bardeesy, Shannon J. Turley, Y. Alan Wang, Lynda Chin, Sarah P. Thayer and Ronald A. DePinho
Cancer Discov July 1 2011 (1) (2) 158-169; DOI: 10.1158/2159-8290.CD-11-0031
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