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Surgical Oncology Laboratory

We have discovered the Ras Association Domain Family 1 Protein, subtype C (abbreviated RASSF1C) to function as an oncogene. In an unexpected finding, we found that RASSF1C actually causes cancer cells to grow and proliferate. Unfortunately, this novel protein has scarcely been studied in cancer. Therefore, we have become very interested to find out what this important molecule does in breast and lung cancer cells—does it function as a tumor suppressor or a growth stimulator?

To learn about the impact of RASSF1C on cancer cell growth and progression, our laboratory has focused on the oncogenic activities of RASSF1C. Our current and previously  published  studies show that: 1) a significant fraction (>50%) of lung cancers are characterized by elevated RASSF1C, 2)  RASSF1C stimulates cell cycle, proliferation, migration of human lung cancer cells, and size/number of tumor spheres produced by lung cancer stem cells (CSC), and 3) RASSF1C is a driver of lung cancer cell metastasis in vivo . 

Also, we found that RASSF1C regulates expression of several genes/proteins important in maintaining a CSC-like phenotype and oncogenesis. RASSF1C induces expression of PIWIL1 and accumulation of β-catenin (both associated with stem cell self-renewal) and regulates expression of PIWI-interacting RNAs (piRNAs) associated with stem cell function. 

In addition, we found that modulation of RASSF1C and PIWIL1 gene expression alters DNA methylation of specific oncogenes and tumor suppressors in lung cancer cells.  Further, small molecules that induce or attenuate RASSF1C expression (ERK inhibitor, CI-1040 and AMPK activator, Trichostatin A) have corresponding effects on PIWIL1 and piRNA gene expression. Moreover, RASSF1C down-regulates a key microRNA (miR-33a-5p) which is known to inhibit lung cancer cell epithelial to mesenchymal transition (EMT) marker gene expression and metastasis . In addition to this, we have also found that RASSF1C up-regulates prolyl 4-hydroxylase alpha-2 (P4HA2) gene expression. P4HA2 protein induces  remodeling of  extracellular matrix (ECM) and cancer cell stemness to drive tumor cell invasion and metastasis. 

Thus, RASSF1C could play a role in microenvironment remodeling, in part, via up-regulation of P4HA2 gene expression to promote lung cancer cell metastasis. Our novel findings, summarized in Figure 1, lead to the hypothesis that RASSF1C promotes lung CSC development and metastasis through modulation of a PIWIL1-piRNA-P4HA2 gene axis. Our studies are novel and significant in that they will: 1) determine whether the RASSF1C-PIWIL1-piRNA-P4HA2 pathway can be targeted to effectively prevent lung cancer metastasis and tumor growth; 2) investigate the impact of RASSF1C on P4HA2 gene regulation and development of EMT and cell stemness; and 3) characterize PIWILI-piRNA complexes and target genes to define the role of the RASSF1C-PIWIL-piRNA-P4HA2 pathway and associated pathways in lung cancer. 

We believe that investigation of this novel pathway will provide important insights into lung cancer stem cell biology and metastasis and could lead to the discovery of novel diagnostic and therapeutic targets for lung cancer.

Research by Yousef G. Amaar and Mark E. Reeves

VA Loma Linda Surgical Oncology

Figure 1. Our current and previous work suggest that RASSF1C modulation of target genes including PIWIL1-piRNA and P4HA2  genes in lung cancer cells contributes to tumor growth and progression.