Cancer-associated fibroblasts promote progression and gemcitabine resistance via the SDF-1/SATB-1 pathway in pancreatic cancer.
Cancer-associated fibroblasts promote progression and gemcitabine resistance via the SDF-1/SATB-1 pathway in pancreatic cancer.
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癌症相关成纤维细胞通过 SDF-1/SATB-1 通路促进胰腺癌进展和吉西他滨耐药
DOI：
10.1038/s41419-018-1104-x
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发表时间：
2018-10-18
影响因子：
9
通讯作者：
Chen R
中科院分区：
文献类型：
--
作者：
Wei L;Ye H;Li G;Lu Y;Zhou Q;Zheng S;Lin Q;Liu Y;Li Z;Chen R
癌症相关成纤维细胞（CAFs）是胰腺肿瘤微环境的主要组成部分，主要被认为是恶性进展的促进因子，但其潜在的分子机制尚不清楚。在这里，我们发现由caf分泌的SDF-1刺激胰腺癌的恶性进展和吉西他滨耐药，部分原因是胰腺癌细胞中SATB-1的旁分泌诱导。CAF分泌的SDF-1上调胰腺癌细胞中SATB-1的表达，这有助于维持CAF的特性，形成一个相互反馈回路。通过实时荧光定量PCR、western blot和免疫组化染色证实SATB-1在人胰腺癌组织和细胞系中过表达，与胰腺癌患者的肿瘤进展和临床预后相关。我们发现SATB-1敲低抑制SW1990和PANC-1细胞的增殖、迁移和侵袭，而SATB-1在Capan-2和BxPC-3细胞中的过表达则具有相反的作用。免疫荧光染色显示，表达SATB-1的SW1990细胞的条件培养基维持了CAFs的局部支持功能。此外，在小鼠异种移植瘤模型中，下调SATB-1抑制肿瘤生长。此外，我们发现胰腺癌细胞中SATB-1的过表达参与了吉西他滨耐药的过程。最后，我们研究了人胰腺癌标本中SDF-1和SATB-1的临床相关性。综上所述，这些发现表明SDF-1/CXCR4/SATB-1轴可能是胰腺癌患者临床干预的潜在新靶点。
Cancer-associated fibroblasts (CAFs), a dominant component of the pancreatic tumor microenvironment, are mainly considered as promotors of malignant progression, but the underlying molecular mechanism remains unclear. Here, we show that SDF-1 secreted by CAFs stimulates malignant progression and gemcitabine resistance in pancreatic cancer, partially owing to paracrine induction of SATB-1 in pancreatic cancer cells. CAF-secreted SDF-1 upregulated the expression of SATB-1 in pancreatic cancer cells, which contributed to the maintenance of CAF properties, forming a reciprocal feedback loop. SATB-1 was verified to be overexpressed in human pancreatic cancer tissues and cell lines by quantitative real-time PCR, western blot, and immunohistochemical staining, which correlated with tumor progression and clinical prognosis in pancreatic cancer patients. We found that SATB-1 knockdown inhibited proliferation, migration, and invasion in SW1990 and PANC-1 cells in vitro, whereas overexpression of SATB-1 in Capan-2 and BxPC-3 cells had the opposite effect. Immunofluorescence staining showed that conditioned medium from SW1990 cells expressing SATB-1 maintained the local supportive function of CAFs. Furthermore, downregulation of SATB-1 inhibited tumor growth in mouse xenograft models. In addition, we found that overexpression of SATB-1 in pancreatic cancer cells participated in the process of gemcitabine resistance. Finally, we investigated the clinical correlations between SDF-1 and SATB-1 in human pancreatic cancer specimens. In summary, these findings demonstrated that the SDF-1/CXCR4/SATB-1 axis may be a potential new target of clinical interventions for pancreatic cancer patients.
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DOI：
10.1158/1078-0432.ccr-15-2888
发表时间：
2017-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Calinescu AA;Yadav VN;Carballo E;Kadiyala P;Tran D;Zamler DB;Doherty R;Srikanth M;Lowenstein PR;Castro MG
通讯作者：
Castro MG
影响因子：
3.8
作者：
Morimoto M;Matsuo Y;Koide S;Tsuboi K;Shamoto T;Sato T;Saito K;Takahashi H;Takeyama H
通讯作者：
Takeyama H
影响因子：
3.5
作者：
Hedner, Charlotta;Gaber, Alexander;Korkocic, Dejan;Nodin, Bjorn;Uhlen, Mathias;Kuteeva, Eugenia;Johannesson, Henrik;Jirstrom, Karin;Eberhard, Jakob
通讯作者：
Eberhard, Jakob
影响因子：
20.3
作者：
Cho, Byung-Sik;Zeng, Zhihong;Konopleva, Marina
通讯作者：
Konopleva, Marina
SATB1促进口腔鳞状细胞癌的肿瘤转移和侵袭
影响因子：
3.8
作者：
Li, Y-C;Bu, L-L;Sun, Z-J
通讯作者：
Sun, Z-J