Original ArticlesSemaphorin-3F suppresses the stemness of colorectal cancer cells by inactivating Rac1
Introduction
Colorectal cancer (CRC) is one of the most common malignancies around the world [1]. Semaphorin-3F (SEMA3F) is a member of axon guidance factors, which plays an important role in the process of neuron axon guidance. Emerging evidence has indicated that some molecules in the family of axon guidance factors, such as Netrin-1 and Slit-2, elicit multiple signaling events in normal stem cells, including mesenchymal stem cell apoptosis and motility [2], [3], hematopoietic stem cell migration [4] and intestinal stem cell proliferation [5]. SEMA3F, characterized as a tumor suppressor, has also been found to be aberrantly expressed and inhibit the progression of many cancers [6], [7]. We have revealed that SEMA3F, which suppresses tumor cell proliferation and migration, is often absent in CRC [8]. However, the underlying mechanisms by which SEMA3F interferes with the progression of CRC remains unknown.
An increasing body of evidence reveals that a small subpopulation of cancer cells is responsible for the initiation and progression of malignancies including CRC [9]. These cells are named as “cancer stem cells (CSCs)” because of their stem-like properties (stemness) including self-renewal, multi-differentiation capability and tumorigenicity potential [10], [11]. Tumorigenesis in immunodeficient mice is regarded as a golden standard for identification of CSCs. So far, some therapeutic strategies against CSCs have shown promising perspective in controlling cancer [12]. However, non-CSCs are most likely to be transformed into CSCs under the pressure of genetic alterations or microenvironmental cues [13], [14], [15]. Therefore, investigation into the regulatory mechanisms governing the stemness of CSCs is crucial for understanding cancer progression and developing new anti-cancer strategies.
We investigated the effect of SEMA3F on the stemness of CRC cells and report the identification of that for key pathways responsible for SEMA3F-mediated CRC stemness. We also determined the expression and the prognostic significance of SEMA3F in CRC specimens.
Section snippets
Tissue specimens and cell culture
Surgical specimens were obtained at operation from 187 patients with colorectal carcinoma (Southwest Hospital, Third Military Medical University) with written consent during the period from 2002 to 2008. The patients received neither chemotherapy nor radiotherapy before surgery. Histological diagnoses were made independently by at least two experienced senior pathologists. All human specimens used in the experiments were approved by Ethics committee of the Third Military Medical University. The
High level of SEMA3F in CRC is associated with longer survival of patients
To investigate the prognostic significance of SEMA3F expression in human CRC, IHC was conducted on tumor sections from 187 patients. As shown in Fig. 1A, SEMA3F expression was observed in the cytoplasm of glandular cells of normal colorectal mucosa as well as in early stage CRC cells. In cancer cells with advanced TNM, the expression of SEMA3F was low or absent (Fig. 1A). The correlation between the level of SEMA3F in tumor and the clinicopathological features of CRC was categorized in Table 1,
Discussion
Emerging evidence indicates that the stemness of cancer cells is responsible for tumor initiation, progression and recurrence [20]. Here, we revealed for the first time a role for SEMA3F in the regulation of stemness of CRC cell. SEMA3F over-expression in CRC reduced LGR5+ CSCs subpopulation and stemness-associated molecules, suggesting that SEMA3F may act as a stemness regulator in CRC. Our study further indicated Rac1 as a critical molecule in the regulation of stemness by SEMA3F. These
Conflict of interest
The authors declare that they have no conflict of interests.
Acknowledgements
This project was supported by grants from the National Basic Research Program of China (973 Program, No. 2010CB529403), the National Natural Science Fund for Youth (No. 81101607 and 81201951). We thank Ms. Qing-hua Ma and Mr. Zeng-tian Sun for their assistance in FACS techniques, and Mrs. Wei Sun and Miss Li-ting Wang (Central Laboratory, Third Military Medical University, Chongqing, China) for their technical assistance in immunofluorescence analysis.
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These authors contributed equally to the study.