Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion

Pancreatic cancer has a high mortality rate due to metastasis. Whereas KRAS is mutated in most pancreatic cancer patients, controlling KRAS or its downstream effectors has not been succeeded clinically. ARL4C is a small G protein whose expression is induced by the Wnt and EGF-RAS pathways. In the present study, we found that ARL4C is frequently overexpressed in pancreatic cancer patients and showed that its localization to invasive pseudopods is required for cancer cell invasion. IQGAP1 was identified as a novel interacting protein for ARL4C. ARL4C recruited IQGAP1 and its downstream effector, MMP14, to invasive pseudopods. Specific localization of ARL4C, IQGAP1, and MMP14 was the active site of invasion, which induced degradation of the extracellular matrix. Moreover, subcutaneously injected antisense oligonucleotide against ARL4C into tumor-bearing mice suppressed metastasis of pancreatic cancer. These results suggest that ARL4C-IQGAP1-MMP14 signaling is activated at invasive pseudopods of pancreatic cancer cells.

Download Full-text

Recruitment of KRAS downstream target ARL4C to membrane protrusions accelerates pancreatic cancer cell invasion

10.1101/2021.02.23.432112 ◽

2021 ◽

Author(s):

Akikazu Harada ◽

Shinji Matsumoto ◽

Yoshiaki Yasumizu ◽

Toshiyuki Akama ◽

Hidetoshi Eguchi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cell ◽

Cell Invasion ◽

Cancer Cell Invasion ◽

Interacting Protein ◽

Downstream Target ◽

Downstream Effector ◽

Downstream Effectors ◽

Specific Localization ◽

Membrane Protrusions

AbstractPancreatic cancer (PC) has a high mortality rate due to metastasis. Whereas KRAS is mutated in most PC patients, controlling KRAS or its downstream effectors has not been succeeded clinically. ARL4C is a small G protein whose expression is induced by the Wnt and EGF–RAS pathways. In the present study, we found that ARL4C is frequently overexpressed in PC patients and showed that its unique localization to membrane protrusions is required for cancer cell invasion. IQGAP1 was identified as a novel interacting protein for ARL4C. ARL4C recruited IQGAP1 and its downstream effector, MMP14, to membrane protrusions. Specific localization of ARL4C, IQGAP1, and MMP14 was the active site of invasion, which induced degradation of the extracellular matrix. Moreover, subcutaneously injected antisense oligonucleotide (ASO) against ARL4C into tumor-bearing mice suppressed metastasis of PC. These results suggest that ARL4C–IQGAP1–MMP14 signaling is activated at membrane protrusions of PC cells.

Download Full-text

Weight-adjusted dalteparin for prevention of vascular thromboembolism in advanced pancreatic cancer patients decreases serum tissue factor and serum-mediated induction of cancer cell invasion

Blood Coagulation & Fibrinolysis ◽

10.1097/mbc.0b013e328338dc49 ◽

2010 ◽

Vol 21 (5) ◽

pp. 452-458 ◽

Cited By ~ 20

Author(s):

Anthony Maraveyas ◽

Camille Ettelaie ◽

Hussein Echrish ◽

Chao Li ◽

Eric Gardiner ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Patients ◽

Tissue Factor ◽

Cancer Cell ◽

Cell Invasion ◽

Advanced Pancreatic Cancer ◽

Cancer Cell Invasion

Download Full-text

Protein kinase D2 induces invasion of pancreatic cancer cells by regulating matrix metalloproteinases

Molecular Biology of the Cell ◽

10.1091/mbc.e13-06-0334 ◽

2014 ◽

Vol 25 (3) ◽

pp. 324-336 ◽

Cited By ~ 36

Author(s):

Christoph Wille ◽

Conny Köhler ◽

Milena Armacki ◽

Arsia Jamali ◽

Ulrike Gössele ◽

...

Keyword(s):

Pancreatic Cancer ◽

Extracellular Matrix ◽

Protein Kinase ◽

Cancer Cell ◽

Cell Invasion ◽

Pancreatic Cancer Cell ◽

Therapeutic Strategies ◽

Cancer Cell Invasion ◽

Pancreatic Cancer Cells

Pancreatic cancer cell invasion, metastasis, and angiogenesis are major challenges for the development of novel therapeutic strategies. Protein kinase D (PKD) isoforms are involved in controlling tumor cell motility, angiogenesis, and metastasis. In particular PKD2 expression is up-regulated in pancreatic cancer, whereas PKD1 expression is lowered. We report that both kinases control pancreatic cancer cell invasive properties in an isoform-specific manner. PKD2 enhances invasion in three-dimensional extracellular matrix (3D-ECM) cultures by stimulating expression and secretion of matrix metalloproteinases 7 and 9 (MMP7/9), by which MMP7 is likely to act upstream of MMP9. Knockdown of MMP7/9 blocks PKD2-mediated invasion in 3D-ECM assays and in vivo using tumors growing on chorioallantois membranes. Furthermore, MMP9 enhances PKD2-mediated tumor angiogenesis by releasing extracellular matrix–bound vascular endothelial growth factor A, increasing its bioavailability and angiogenesis. Of interest, specific knockdown of PKD1 in PKD2-expressing pancreatic cancer cells further enhanced the invasive properties in 3D-ECM systems by generating a high-motility phenotype. Loss of PKD1 thus may be beneficial for tumor cells to enhance their matrix-invading abilities. In conclusion, we define for the first time PKD1 and 2 isoform–selective effects on pancreatic cancer cell invasion and angiogenesis, in vitro and in vivo, addressing PKD isoform specificity as a major factor for future therapeutic strategies.

Download Full-text

MicroRNA-301a promotes pancreatic cancer invasion and metastasis through the JAK/STAT3 signaling pathway by targeting SOCS5

Carcinogenesis ◽

10.1093/carcin/bgz121 ◽

2019 ◽

Vol 41 (4) ◽

pp. 502-514 ◽

Cited By ~ 9

Author(s):

Hui Hu ◽

Qin Zhang ◽

Weiqun Chen ◽

Tangwei Wu ◽

Shuiyi Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Patients ◽

Cancer Cell ◽

Cell Invasion ◽

Pancreatic Cancer Cell ◽

Cancer Invasion ◽

Janus Kinase ◽

Cancer Cell Invasion ◽

Invasion And Metastasis ◽

And Migration

AbstractPancreatic cancer is one of the most lethal digestive malignant tumors. We had previously found that microRNA-301a (miR-301a) is a oncogenic microRNA whose recognized conduce to nuclear factor-kappa B (NF-κB) activation in pancreatic cancer, yet the underlying mechanisms of miR-301a in promoting pancreatic cancer invasion and migration is obscure. In this work we found that high expression of miR-301a in human pancreatic cancer patients is related to poor survival. Overexpression of miR-301a enhances pancreatic cancer cell invasion, angiogenesis and migration, whereas inhibition of miR-301a suppresses pancreatic cancer cell invasion and reduces orthotopic pancreatic tumor growth and metastasis. Furthermore, suppressor of cytokine signaling 5 (SOCS5) is identified as a target gene of miR-301a. We found that miR-301a suppressed the expression of SOCS5 leads to janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) activation and is related to poor overall survival of pancreatic cancer patients. Taken together, our data show for the first time that the feedback loop between miR-301a and JAK/STAT3 pathway may play a significant role in pancreatic cancer invasion and metastasis. Targeting the loop may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for pancreatic cancer.

Download Full-text