CD44 regulates cell proliferation, migration, and invasion via modulation of c-Src transcription in human breast cancer cells

Nam, Kyoung Won; Oh, Sunhwa; Lee, Kyung-min; Yoo, Sehoon; Shin, Incheol

doi:10.1016/j.cellsig.2015.05.002

Cited by 97 publications

(80 citation statements)

References 40 publications

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“…These results implied p38 as the critical mediator of MCP-1 expression induced by MIF. CD44 can trigger Syk activation in neutrophils, which promotes phosphorylation of p3847, and its knockdown suppresses both mRNA and protein levels of c-Src and its downstream MAPK pathway48. Therefore, we speculated that MIF might amplify the p38 signaling pathway through CD44, and then promote MCP-1 expression in hepatocytes.…”

Section: Discussionmentioning

confidence: 97%

Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury

Xie

Yang

Tian

et al. 2016

Sci Rep

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Macrophage migration inhibitor factor (MIF), a multipotent innate immune mediator, is an upstream component of the inflammatory cascade in diseases such as liver disease. Monocyte chemoattractant protein-1 (MCP-1), a highly representative chemokine, is critical in liver disease pathogenesis. We investigated the role of MIF in regulating hepatocytic MCP-1 expression. MIF and MCP-1 expression were characterized by immunochemistry, RT-PCR, ELISA, and immunoblotting in CCl4-treated mouse liver and isolated hepatocytes. MIF was primarily distributed in hepatocytes, and its expression increased upon acute liver injury. Its expression was also increased in injured hepatocytes, induced by LPS or CCl4, which mimic liver injury in vitro. MIF was expressed earlier than MCP-1, strongly inducing hepatocytic MCP-1 expression. Moreover, the increase in MCP-1 expression induced by MIF was inhibited by CD74- or CD44-specific siRNAs and SB203580, a p38 MAPK inhibitor. Further, CD74 or CD44 deficiency effectively inhibited MIF-induced p38 activation. MIF inhibitor ISO-1 reduced MCP-1 expression and p38 phosphorylation in CCl4-treated mouse liver. Our results showed that MIF regulates MCP-1 expression in hepatocytes of injured liver via CD74, CD44, and p38 MAPK in an autocrine manner, providing compelling information on the role of MIF in liver injury, and implying a new regulatory mechanism for liver inflammation.

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Section: Discussionmentioning

confidence: 97%

Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury

Xie

Yang

Tian

et al. 2016

Sci Rep

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“…M2 macrophages-secreted osteoactivin/glycoprotein non-metastatic melanoma protein B was reported to enhance the viability, proliferation and migration of mesenchymal stem cells through extracellular signal-regulated kinase (ERK) and AKT signaling pathways via CD44 (16). In addition, biological changes induced by CD44 silencing were revealed to be mediated by cumulative downregulation of c-Jun, Sp1 and c-Src in human breast cancer cells (17). The molecular mechanisms underlying the effects of CD44 overexpression on ovarian cancer cells remain to be fully clarified.…”

Section: Discussionmentioning

confidence: 98%

Effects of CD44 and E‑cadherin overexpression on the proliferation, adhesion and invasion of ovarian cancer cells

et al. 2017

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Abstract. CD44 is a prognostic indicator of shorter survival time in ovarian cancer. E-cadherin fragmentation promotes the progression of ovarian cancer. However, the effects of CD44 and E-cadherin overexpression on ovarian cancer cells have remained elusive. The present study aimed to investigate the effects of overexpression of CD44 and E-cadherin on cell proliferation, adhesion and invasion of SKOV-3 and OVCAR-3 ovarian cancer cells. Overexpression of CD44 and E-cadherin was achieved by transfecting SKOV-3 and OVCAR-3 cells with viruses carrying the CD44 or E-cadherin gene, respectively. Expression of CD44 and E-cadherin was detected by western blot analysis. The proliferation of SKOV-3 and OVCAR-3 cells was measured by a Cell Counting Kit-8 at 0, 24 and 48 h after viral transfection. The adhesion ability of SKOV-3 and OVCAR-3 cells to the endothelial layer was detected. A Transwell invasion assay was utilized to assess the invasion ability of the cells. Overexpression of CD44 and E-cadherin in SKOV-3 and OVCAR-3 cells was confirmed by western blot. Compared with the blank or negative control groups, the CD44 overexpression groups of SKOV-3 and OVCAR-3 cells exhibited an increased cell proliferation rate at 24 and 48 h, whereas overexpression of E-cadherin did not alter the proliferation of these cells. Furthermore, compared with the blank and negative control groups, the cell adhesion and invasion ability in the CD44 overexpression groups of SKOV-3 and OVCAR-3 cells was markedly higher. There were no significant differences in adhesion ability between the E-cadherin overexpression group and the blank/negative control group. Of note, overexpression of E-cadherin decreased the invasive ability of SKOV-3 and OVCAR-3 cells. In conclusion, Overexpression of CD44 increased the proliferation, adhesion and invasion of ovarian cancer cells, while overexpression of E-cadherin decreased the invasion of ovarian cancer cells. IntroductionOvarian cancer is a common malignant tumor type of the female reproductive system with a high mortality rate. The 5-year survival rate of patients with ovarian cancer is 25-30% (1). Although progress has been made in the treatment of ovarian cancer, the mortality rate remains high. The majority of ovarian cancer patients have tumor metastasis at the time-point of diagnosis, and tumor invasion and metastasis are important causes of treatment failure (2). Therefore, investigation of the molecular mechanisms involved in tumor proliferation, adhesion and invasion is of great importance for improving the therapeutic effectiveness of ovarian cancer treatments.CD44 is a transmembrane protein that mediates cell-cell interactions as well as cell adhesion and migration. It is widely expressed on the cell surface (3). CD44 participates in numerous biological processes such as tumor metastasis, hematopoiesis, lymphocyte activation, recirculation and homing. CD44 is a receptor for hyaluronic acid and interacts with other ligands, such as matrix metalloproteinases, collagens and osteopontin (3). Posit...

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“…Correspondingly, a CD44kd is accompanied by Src, paxillin, FAK, c-Jun and transcription factor Sp1 downregulation, where Sp1 contributes to Src transcription. This provides an alternative pathway of CD44-promoted motility, which relies mostly on the engagement of CD44 in the JNK pathway activation (Nam et al, 2015). In line with these findings and pointing toward a special contribution of CD44v isoforms, migration of CD44v6/v7ko-HSPC toward the niche is impaired, due to the failure to bind to FN (Naor et al, 1997), FN binding promoting the association of CD44v6 with α4β1.…”

Section: Cd44/cd44v6 Associations Contributing To Cic Motility and Inmentioning

confidence: 99%

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

Wang

Zhao

Hackert

et al. 2018

Front. Cell Dev. Biol.

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Metastasis is the leading cause of cancer death, tumor progression proceeding through emigration from the primary tumor, gaining access to the circulation, leaving the circulation, settling in distant organs and growing in the foreign environment. The capacity of a tumor to metastasize relies on a small subpopulation of cells in the primary tumor, so called cancer-initiating cells (CIC). CIC are characterized by sets of markers, mostly membrane anchored adhesion molecules, CD44v6 being the most frequently recovered marker. Knockdown and knockout models accompanied by loss of tumor progression despite unaltered primary tumor growth unraveled that these markers are indispensable for CIC. The unexpected contribution of marker molecules to CIC-related activities prompted research on underlying molecular mechanisms. This review outlines the contribution of CD44, particularly CD44v6 to CIC activities. A first focus is given to the impact of CD44/CD44v6 to inherent CIC features, including the crosstalk with the niche, apoptosis-resistance, and epithelial mesenchymal transition. Following the steps of the metastatic cascade, we report on supporting activities of CD44/CD44v6 in migration and invasion. These CD44/CD44v6 activities rely on the association with membrane-integrated and cytosolic signaling molecules and proteases and transcriptional regulation. They are not restricted to, but most pronounced in CIC and are tightly regulated by feedback loops. Finally, we discuss on the engagement of CD44/CD44v6 in exosome biogenesis, loading and delivery. exosomes being the main acteurs in the long-distance crosstalk of CIC with the host. In brief, by supporting the communication with the niche and promoting apoptosis resistance CD44/CD44v6 plays an important role in CIC maintenance. The multifaceted interplay between CD44/CD44v6, signal transducing molecules and proteases facilitates the metastasizing tumor cell journey through the body. By its engagement in exosome biogenesis CD44/CD44v6 contributes to disseminated tumor cell settlement and growth in distant organs. Thus, CD44/CD44v6 likely is the most central CIC biomarker.

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CD44 regulates cell proliferation, migration, and invasion via modulation of c-Src transcription in human breast cancer cells

Cited by 97 publications

References 40 publications

Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury

Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury

Effects of CD44 and E‑cadherin overexpression on the proliferation, adhesion and invasion of ovarian cancer cells

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

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