Abstract

Metastatic colorectal cancer (mCRC) is characterized by the expression of cellular oncogenes, the loss of tumor suppressor gene function. Therefore, identifying integrated signaling between onco-suppressor genes may facilitate the development of effective therapy for mCRC. To investigate these pathways we utilized cell lines and patient derived organoid models for analysis of gene/protein expression, gene silencing, overexpression, and immunohistochemical analyses. An inverse relationship in expression of oncogenic FoxM1 and tumor suppressor RASSF1A was observed in various stages of CRC. This inverse correlation was also observed in mCRC cells lines (T84, Colo 205) treated with Akt inhibitor. Inhibition of FoxM1 expression in mCRC cells as well as in our ex vivo model resulted in increased RASSF1A expression. Reduced levels of RASSF1A expression were found in normal cells (RWPE-1, HBEpc, MCF10A, EC) stimulated with exogenous VEGF165. Downregulation of FoxM1 also coincided with increased YAP phosphorylation, indicative of tumor suppression. Conversely, downregulation of RASSF1A coincided with FoxM1 overexpression. These studies have identified for the first time an integrated signaling pathway between FoxM1 and RASSF1A in mCRC progression, which may facilitate the development of novel therapeutic options for advanced colon cancer therapy.

Highlights

  • More than 90% of all cancer-associated deaths are caused by metastasis

  • To determine if RASSF1A suppression is due to angiogenic induction we to determine if RASSF1A suppression is due to angiogenic induction we stimulated stimulated normal cell lines with normal cell lines with different different concentrations of exogenous VEGF165 (12.5 and 25 ng/mL), a known inducer of angiogenic concentrations of exogenous VEGF165 (12.5 and 25 ng/mL), a known inducer of angiogenic signaling

  • We further evaluated FoxM1 and RASSF1A expression in colorectal cancer (CRC) using tissue arrays containing the specturm of colon cancer stages as well as normal colon tissue (NAT)

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Summary

Introduction

More than 90% of all cancer-associated deaths are caused by metastasis. Metastatic colon cancer (mCRC) is the third most lethal disease in the United States. 50% of patients will develop metastasis during the course of colon cancer and the five-year survival is only around. In early stages of the disease, cancer lesions can be removed by surgical excision. In more advanced cases cytotoxic drugs such as 5FU, oxaliplatin, and irinotecan are used as a first line of Cancers 2019, 11, 199; doi:10.3390/cancers11020199 www.mdpi.com/journal/cancers. Patients often develop resistance to these drugs within 3–12 months [3]. Understanding the cellular mechanisms that regulate metastasis is vital to the development of effective cancer therapies

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