Olfactomedin 4 Suppresses Tumor Growth and Metastasis of Mouse Melanoma Cells through Downregulation of Integrin and MMP Genes

Abstract

Olfactomedin 4 (OLFM4) is highly expressed in gastrointestinal cancers and has an anti-apoptotic function. The roles of OLFM4 in tumor growth and metastasis and how it functions in these processes remain elusive. We investigated the function of OLFM4 in tumor growth and metastasis using B16F10 mouse melanoma cells as an experimental system. Our results showed that OLFM4 had no positive effect on cell viability or cell cycle progression in B16F10 cells. However, it significantly suppressed the tumorigenicity of B16F10 cells, i.e., intradermal primary tumor growth and lung metastasis. OLFM4 also suppressed the migration and invasion of B16F10 cells in vitro. For further insight into the mechanisms underlying OLFM4-mediated suppression of tumor progression, we examined the effect of OLFM4 on the expression of integrin and matrix metalloproteinase (MMP), both of which are involved in tumor progression. Overexpression of OLFM4 clearly reduced the expression levels of integrin α1, integrin α4, integrin α5, integrin α6, and MMP9. Moreover, forced expression of MMP9 attenuated the inhibitory activity of OLFM4 on migration and invasiveness. Our findings provide the experimental evidence that OLFM4 may function as a tumor suppressor and an anti-metastatic gene during tumor progression.

Plasma olfactomedin 4 level in peripheral blood and its association with clinical features of breast cancer

“…The results from the present study indicated that plasma OLFM4 levels in breast cancer patients were associated with histological tumor differentiation. High plasma OLFM4 levels were detected in patients with high histological grade, which was consistent with data from previous studies on pancreatic (5) and gastric cancer (9,11).…”

“…A study has reported that OLFM4 levels in peripheral blood are significantly higher in gastric cancer patients prior to surgery compared with normal individuals (9). An opposite trend was observed in the present study, that is, the plasma OLFM4 expression levels were far lower in breast cancer patients compared with healthy controls.…”

“…This percentage is lower compared with the values reported in colon (90%) and lung (85%) cancer tissue specimens over the same period (10). Furthermore, it was thought that the OLFM4 expression level has no significant association with common clinical variables (9,10). However, a limited number of studies have reported OLFM4 gene expression in breast cancer patients, and the expression levels of this gene in the peripheral blood of tumor patients remain to be documented (1,10,11,17).…”

“…Liu et al (8) reported reduced expression of OLFM4 in patients with advanced colon cancer (stages III and IV), lymph node metastases and distant metastases compared with normal colon tissue. Using a mouse melanoma model, Park et al (9) observed that OLFM4 suppresses tumor growth and metastasis by downregulating Studies have shown relatively low levels of OLFM4 expression in normal tissues of several organs, including the stomach, colon and pancreas. Whereas, to varying degrees, upregulation of OLFM4 expression has been implicated in gastric, pancreatic, lung, colon, rectal, and head/neck squamous cell cancer (5,(10)(11)(12).…”

Low expression of olfactomedin 4 correlates with poor prognosis in smoking patients with non–small cell lung cancer

“…OLFM4 exhibited the same expression in the diverse differentiation of NSCLC and was highly expressed in tissues of NSCLC without lymph node metastasis. These observations indicated that OLFM4 may function as a tumor suppressor and an antimetastatic gene during tumor progression [24]. However, a high rate of OLFM4 overexpression was found in NSCLC patients with positive Fig.…”