TSPAN2 Is Involved in Cell Invasion and Motility during Lung Cancer Progression

Otsubo, Chihiro; Otomo, Ryo; Miyazaki, Makoto; Matsushima-Hibiya, Yuko; Kohno, Takashi; Iwakawa, Reika; Takeshita, Fumitaka; Okayama, Hirokazu; Ichikawa, Hitoshi; Saya, Hideyuki; Kiyono, Tohru; Ochiya, Takahiro; Tashiro, Fumio; Nakagama, Hitoshi; Yokota, Jun; Enari, Masato

doi:10.1016/j.celrep.2014.03.027

Cited by 34 publications

(44 citation statements)

References 53 publications

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“…Genes that are derepressed by the down-regulation of p53, such as MDR1 (37), CD44 (38), TCTP (39), and TSPAN2 (40), have been identified, and we found that TSPAN12 was derepressed by the down-regulation of p53 in fibroblasts. The mechanism underlying the transcriptional derepression of TSPAN12 through the down-regulation of p53 is complex, and even though a reporter assay using the TSPAN12 promoter region (−1,000 to −1) and ChIP analysis of the proximal TSPAN12 promoter region (−230 to −1) using various specific primers were conducted, we could not confirm that TSPAN12 was a direct p53-target gene.…”

Section: Discussionmentioning

confidence: 88%

TSPAN12 is a critical factor for cancer–fibroblast cell contact-mediated cancer invasion

Otomo

Otsubo

Matsushima-Hibiya³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Communication between cancer cells and their microenvironment controls cancer progression. Although the tumor suppressor p53 functions in a cell-autonomous manner, it has also recently been shown to function in a non-cell-autonomous fashion. Although functional defects have been reported in p53 in stromal cells surrounding cancer, including mutations in the p53 gene and decreased p53 expression, the role of p53 in stromal cells during cancer progression remains unclear. We herein show that the expression of α-smooth muscle actin (α-SMA), a marker of cancerassociated fibroblasts (CAFs), was increased by the ablation of p53 in lung fibroblasts. CAFs enhanced the invasion and proliferation of lung cancer cells when cocultured with p53-depleted fibroblasts and required contact between cancer and stromal cells. A comprehensive analysis using a DNA chip revealed that tetraspanin 12 (TSPAN12), which belongs to the tetraspanin protein family, was derepressed by p53 knockdown. TSPAN12 knockdown in p53-depleted fibroblasts inhibited cancer cell proliferation and invasion elicited by coculturing with p53-depleted fibroblasts in vitro, and inhibited tumor growth in vivo. It also decreased CXC chemokine ligand 6 (CXCL6) secretion through the β-catenin signaling pathway, suggesting that cancer cell contact with TSPAN12 in fibroblasts transduced β-catenin signaling into fibroblasts, leading to the secretion of CXCL6 to efficiently promote invasion. These results suggest that stroma-derived p53 plays a pivotal role in epithelial cancer progression and that TSPAN12 and CXCL6 are potential targets for lung cancer therapy.cancer-associated fibroblasts | cancer invasion | cancer-stromal cell interaction | p53 | tetraspanin family

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Section: Discussionmentioning

confidence: 88%

TSPAN12 is a critical factor for cancer–fibroblast cell contact-mediated cancer invasion

Otomo

Otsubo

Matsushima-Hibiya³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In these cells, elevation of ROS levels has been shown to promote proliferation and enhance motility and invasion [18,19]. Reciprocally, antioxidants have been for a long time considered as tumor suppressing agents [20-24]. However, recently the opposite functions of antioxidants have been reported.…”

Section: Oxidative Stressmentioning

confidence: 99%

“…Accordingly, overproduction of ROS was identified as an inhibitor of tumor cell proliferation, viability and various transformed phenotypes [20-24;33-36]. The latter effects of ROS caused significant attention to the mechanisms regulating their production and utilization in cancer cells [35,36], and the potential exploitation of these mechanisms in novel antineoplastic agents [37].…”

Section: Oxidative Stressmentioning

confidence: 99%

Oxidative stress and proteasome inhibitors in multiple myeloma

Lipchick

Fink

Nikiforov

2016

Pharmacological Research

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Multiple myeloma is a form of plasma cell neoplasm that accounts for approximately 10% of all hematological malignancies. Recently, several novel drugs have been discovered that almost doubled the overall survival of multiple myeloma patients. One of these drugs, the first-in-class proteasome inhibitor bortezomib (Velcade) has demonstrated remarkable response rates in multiple myeloma patients, and yet, currently this disease remains incurable. The major factor undermining the success of multiple myeloma treatment is a rapidly emerging resistance to the available therapy. Thus, the development of stand-alone or adjuvant anti-myeloma agents becomes of paramount importance. Overproduction of intracellular reactive oxygen species (ROS) often accompanies malignant transformation due to oncogene activation and/or enhanced metabolism in tumor cells. As a result, these cells possess higher levels of ROS and lower levels of antioxidant molecules compared to their normal counterparts. Unbalanced production of ROS leads to oxidative stress which, if left unchecked, could be toxic for the cell. In multiple myeloma cells where high rates of immunoglobulin synthesis is an additional factor contributing to overproduction of ROS, further induction of oxidative stress can be an effective strategy to cope with this disease. Here we will review the available data on the role of oxidative stress in the cytotoxicity of proteasome inhibitors and the use of ROS-inducing compounds as anti-myeloma agents.

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“…In malignancy, strong expression of Tspan2 is associated with poor prognosis in lung cancer and it has been linked to disease progression associated with p53 inactivation [77]. Mutation of the tumour suppressor p53 is often observed in invasive tumours and contributes towards cancer metastasis by modulating EMT [78].…”

Section: Tspan2 and Cancer Progressionmentioning

confidence: 99%

“…Knockdown of Tspan2 reduced invasiveness and motility in p53-depleted SAECs or cancer cell lines with p53 mutations, whereas overexpression of Tspan2 enhanced these attributes. Knockdown of Tspan2 was also shown to reduce lung metastasis in a mouse model [77]. Co-immunoprecipitation identified CD44 as one of the proteins interacting with Tspan2 and the role of this protein, which is known to interact with other tetraspanins, was investigated further.…”

Section: Tspan2 and Cancer Progressionmentioning

confidence: 99%

Tspan2: a tetraspanin protein involved in oligodendrogenesis and cancer metastasis

Yaseen

Monk

Partridge

2017

Biochemical Society Transactions

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Tetraspanin 2 (Tspan2) is one of the less well-characterised members of the tetraspanin superfamily, and its precise function in different human tissue types remains to be explored. Initial studies have highlighted its possible association in neuroinflammation and carcinogenesis. In the central nervous system, Tspan2 may contribute to the early stages of the oligodendrocyte differentiation into myelin-forming glia. Furthermore, in human lung cancer, Tspan2 could be involved in the progression of the tumour metastasis by modulating cancer cell motility and invasion functions. In this review, we discuss the available evidence for the potential role of Tspan2 and introduce possible strategies for disease targeting.

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TSPAN2 Is Involved in Cell Invasion and Motility during Lung Cancer Progression

Cited by 34 publications

References 53 publications

TSPAN12 is a critical factor for cancer–fibroblast cell contact-mediated cancer invasion

TSPAN12 is a critical factor for cancer–fibroblast cell contact-mediated cancer invasion

Oxidative stress and proteasome inhibitors in multiple myeloma

Tspan2: a tetraspanin protein involved in oligodendrogenesis and cancer metastasis

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