Involvement of Epithelial Cell Transforming Sequence-2 Oncoantigen in Lung and Esophageal Cancer Progression

Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and represents one of the deadliest forms of human cancers. Previous studies showed that activation of Yes-associated protein 1 (YAP1) plays a key role in malignant transformation in the pancreas. In this study, we found that YAP1 regulates the expression of epithelial cell transforming 2 (ECT2), a guanine nucleotide exchange factor for Rho-like GTPases. By immunohistochemistry analysis of human tissues, we show that ECT2 is highly expressed in primary PDAC and liver metastasis but not in normal pancreas. These correlations were also observed in a mouse model of PDAC, where pancreatic transformation is driven by mutants of Kras and Trp53. Notably, nuclear ECT2 is upregulated in the transition from pre-neoplastic lesions to PDAC. High levels of YAP1 or ECT2 expression correlates with poor overall survival rate of PDAC patients. We further demonstrate that ECT2 is required for pancreatic cancer cell proliferation and migration in vitro. Finally, using a syngeneic orthotopic xenograft mouse model for pancreatic cancer, we found that ablation of ECT2 expression reduces pancreatic cancer growth and dissemination to the liver. These findings highlight a critical role of ECT2 in promoting pancreatic cancer growth and metastasis and provides insights into development of novel methods for early detection and treatment.

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Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

Scientific Reports ◽

10.1038/s41598-021-81465-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ryoichi Katsube ◽

Kazuhiro Noma ◽

Toshiaki Ohara ◽

Noriyuki Nishiwaki ◽

Teruki Kobayashi ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Near Infrared ◽

Fibroblast Activation Protein ◽

Therapeutic Resistance ◽

Fibroblast Activation ◽

Human Esophageal Cancer

AbstractCancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

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NETO2 promotes esophageal cancer progression by inducing proliferation and metastasis via PI3K/AKT and ERK pathway

International Journal of Biological Sciences ◽

10.7150/ijbs.53795 ◽

2021 ◽

Vol 17 (1) ◽

pp. 259-270

Author(s):

Jia-cheng Xu ◽

Tian-yin Chen ◽

Le-tai Liao ◽

Tao Chen ◽

Quan-lin Li ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Progression ◽

Erk Pathway ◽

Proliferation And Metastasis

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[Retracted] Oncogenic role of epithelial cell transforming sequence 2 in lung adenocarcinoma cells

Experimental and Therapeutic Medicine ◽

10.3892/etm.2021.10220 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Hongyi Tan ◽

Xiaoshan Wang ◽

Xiaogang Yang ◽

Haitao Li ◽

Ben Liu ◽

...

Keyword(s):

Epithelial Cell ◽

Lung Adenocarcinoma ◽

Adenocarcinoma Cells ◽

Lung Adenocarcinoma Cells ◽

Cell Transforming

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Epigenetically associated CCL20 upregulation correlates with esophageal cancer progression and immune disorder

Pathology - Research and Practice ◽

10.1016/j.prp.2021.153683 ◽

2021 ◽

pp. 153683

Author(s):

Hongxing Nan ◽

Lisha Zhou ◽

Weihua Liang ◽

Jin Meng ◽

Ke Lin ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Progression ◽

Immune Disorder

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Polymerase-δ-interacting protein 2 activates the RhoGEF epithelial cell transforming sequence 2 in vascular smooth muscle cells

AJP Cell Physiology ◽

10.1152/ajpcell.00208.2018 ◽

2019 ◽

Vol 316 (5) ◽

pp. C621-C631 ◽

Cited By ~ 1

Author(s):

Lauren Parker Huff ◽

Daniel Seicho Kikuchi ◽

Elizabeth Faidley ◽

Steven J. Forrester ◽

Michelle Z. Tsai ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Smooth Muscle ◽

Epithelial Cell ◽

Vascular Smooth Muscle ◽

Vascular Smooth Muscle Cells ◽

Oxygen Species ◽

Interacting Protein ◽

Rho Family Gtpases ◽

Rho Family ◽

Cell Transforming

Polymerase-δ-interacting protein 2 (Poldip2) controls a wide variety of cellular functions and vascular pathologies. To mediate these effects, Poldip2 interacts with numerous proteins and generates reactive oxygen species via the enzyme NADPH oxidase 4 (Nox4). We have previously shown that Poldip2 can activate the Rho family GTPase RhoA, another signaling node within the cell. In this study, we aimed to better understand how Poldip2 activates Rho family GTPases and the functions of the involved proteins in vascular smooth muscle cells (VSMCs). RhoA is activated by guanine nucleotide exchange factors. Using nucleotide-free RhoA (isolated from bacteria) to pulldown active RhoGEFs, we found that the RhoGEF epithelial cell transforming sequence 2 (Ect2) is activated by Poldip2. Ect2 is a critical RhoGEF for Poldip2-mediated RhoA activation, because siRNA against Ect2 prevented Poldip2-mediated RhoA activity (measured by rhotekin pulldowns). Surprisingly, we were unable to detect a direct interaction between Poldip2 and Ect2, as they did not coimmunoprecipitate. Nox4 is not required for Poldip2-driven Ect2 activation, as Poldip2 overexpression induced Ect2 activation in Nox4 knockout VSMCs similar to wild-type cells. However, antioxidant treatment blocked Poldip2-induced Ect2 activation. This indicates a novel reactive oxygen species-driven mechanism by which Poldip2 regulates Rho family GTPases. Finally, we examined the function of these proteins in VSMCs, using siRNA against Poldip2 or Ect2 and determined that Poldip2 and Ect2 are both essential for vascular smooth muscle cell cytokinesis and proliferation.

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Hsa_circ_0004370 promotes esophageal cancer progression through miR-1294/LASP1 pathway

Bioscience Reports ◽

10.1042/bsr20182377 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 11

Author(s):

Zhenyang Zhang ◽

Wenwei Lin ◽

Lei Gao ◽

Keqing Chen ◽

Chuangcai Yang ◽

...

Keyword(s):

Esophageal Cancer ◽

Cell Lines ◽

Cancer Progression ◽

Multiple Roles ◽

Luciferase Reporter ◽

Circular Rnas ◽

Rescue Effect ◽

Rna Immunoprecipitation ◽

Si Rna ◽

Proliferation And Invasion

AbstractCircular RNAs (circRNAs) formed by back-splicing play multiple roles in the occurrence and development of cancer. Here, we found that hsa_circ_0004370 was up-regulated in both esophageal cancer (EC) tissues and cell lines. Loss function of hsa_circ_0004370 by si-RNA significantly suppressed proliferation and invasion and promoted apoptosis in both EC cell lines. The sponging of miR-1294 by hsa_circ_0004370 was bioinformatically predicted and subsequently verified by luciferase reporter assay and RNA immunoprecipitation assay. Further, hsa_circ_0004370 involved in the up-regulation of LASP1 by sponging miR-1294. Besides, the inhibition of the down-regulated hsa_circ_0004370 on cell malignant behaviors was rescued by miR-1294 inhibitor. Finally, this rescue effect was abrogated by suppressing the expression of LASP1. The results present here suggest that hsa_circ_0004370 functions as an oncogene on cell proliferation, apoptosis, and invasion via miR-1294/LASP1 axis.

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