Abstract
Tiam1 is a rac1-specific guanine nucleotide exchange factor, and Tiam1-rac1 is involved in a number of cellular processes. Rac1 and RhoA act as molecular switches that cycle between GTP- and GDP-bound states to balance the activities of rac1 and RhoA. The downregulation of rac1 activity leads to upregulation of RhoA activity, which promotes invasion and migration of pancreatic cancers cells. At present, however, the role of Tiam1-rac1 and RhoA in pancreatic cancers is not fully understood. We found that Tiam1 was upregulated in pancreatic cancers and was significantly expressed in tumors without lymph node involvement or distant metastasis compared with cancers where there was involvement. Although Tiam1-rac1 signaling promoted pancreatic cancer cell proliferation and tumor growth via the Wnt signaling pathway in vitro and in vivo, inhibiting Tiam1-rac1 signaling did not prolong the overall survival time in vivo. This provided evidence that there was a balance between rac1 and RhoA activities in pancreatic cancers. Furthermore, only the combined inhibition of Tiam1-rac1 and RhoA had a beneficial effect on the growth of pancreatic cancers in vivo. Taken together, these results suggest that the progression of pancreatic tumors is partially controlled by the balance between Tiam1-rac1 and RhoA.
Highlights
Pancreatic cancer is the fourth most common cause of cancer-related death worldwide and is always associated with a poor prognosis [1]
Poor clinical outcomes may be due to most patients being diagnosed with advanced disease with extensive metastasis, high resistance of tumors to chemotherapy, and lack of effective chemotherapeutic agents [2]
Immunohistochemical staining of tissue sections showed that normal pancreas tissue samples were negative for Tiam1, benign tumors were weakly positive, and adenocarcinomas were strongly positive (Fig. 1A)
Summary
Pancreatic cancer is the fourth most common cause of cancer-related death worldwide and is always associated with a poor prognosis [1]. Poor clinical outcomes may be due to most patients being diagnosed with advanced disease with extensive metastasis, high resistance of tumors to chemotherapy, and lack of effective chemotherapeutic agents [2]. Investigation of the underlying mechanisms driving pancreatic cancer progression may reveal molecular targets for novel treatment strategies. Tiam (T lymphoma invasion and metastasis 1) is a rac1specific guanine nucleotide exchange factor and is believed to act as an oncogene in many cancers [3,4,5,6]. Tiam maintains the specificity of rac toward specific downstream effector pathways, whereas rac regulates cell survival and cell-cycle progression [7, 8]. Tiam1-rac is a critical component in the biology of human tumors, in both transformed
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