Tspan15 Is a New Stemness‐Related Marker in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the second cause of cancer‐related deaths worldwide. A clearer understanding of the molecular mechanisms underlying tumor growth and invasiveness remains crucial for developing new therapies. Here, the expression of tetraspanins, a family of plasma membrane organizers involved in tumor progression, has been addressed. Integrative approaches combining transcriptomics and bioinformatics allow demonstrating the induced and heterogeneous expression of Tspan15 in HCC. Tspan15 positive tumors exhibit signatures related to hepatic progenitor cells as well as recurrence of cancer. Immunohistochemistry experiments confirm Tspan15 expression in the subset of HCC expressing stemness‐related markers such as EpCAM and Cytokeratin‐19. Functional networks reveal that most of these genes expressed in correlation to Tspan15 support cell proliferation. Furthermore, Tspan15 overexpression in the hepatoma cell line HepG2 significantly increases cell proliferation. A quantitative proteomic analysis of the secretome reveals a higher abundance of the protein connective tissue growth factor (CTGF), a pleiotropic matricellular signaling protein. Proteomic profiling of Tspan15 complexes allows identifying numerous membrane proteins including several growth factor receptors. Finally, Tspan15 increases ERK1/2 phosphorylation that directly controls CTGF expression and secretion. In conclusion, Tspan15 is a new stemness‐related marker in HCC which exhibits high potential of tumor growth and recurrence.

Tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex

“…Indeed, ADAM10 was almost 400 times more abundant in Tspan15 immunoprecipitates from wild-type cells versus control Tspan15-knockout cells, and the only other protein identified above the false discovery rate threshold was Tspan15 itself. These data are consistent with two previous studies in which GFP-tagged Tspan15 was expressed in U2OS or HepG2 cells, which were lysed in relatively non-stringent 1% Brij97 and Tspan15 immunoprecipitated via the GFP tag (Jouannet et al 2016; Sidahmed-Adrar et al 2019). For example, mass spectrometry identified ADAM10 as 15-fold more abundant than any other Tspan15-interacting proteins (Jouannet et al 2016).…”

“…Interestingly, gene expression data suggests that Tspan15 is strongly upregulated in cholangiocarcinoma and pancreatic adenocarcinoma (Tang et al 2019), and is a marker of poor prognosis in pancreatic, renal and liver cancer (Uhlen et al 2017). Moreover, Tspan15 has been recently implicated in oral squamous cell carcinoma (Hiroshima et al 2019) and hepatocellular carcinoma (Sidahmed-Adrar et al 2019).…”

“…Tspan15 is best characterised by its capacity to promote ADAM10 cleavage of N-cadherin in cell lines and in vivo (Prox et al 2012; Jouannet et al 2016; Noy et al 2016; Seipold et al 2018). Tspan15 is also upregulated, and is a marker of poor prognosis, in certain cancers (Zhang et al 2018; Hiroshima et al 2019; Sidahmed-Adrar et al 2019) and promotes cancer progression in a mouse model (Zhang et al 2018). The aims of this study were to generate the first Tspan15 mAbs and to test three hypotheses that would support the theory that Tspan15 and ADAM10 exist together as a scissor complex: first, that ADAM10 is the principal Tspan15-interacting protein; second, that Tspan15 expression requires ADAM10; and third, that covalently linking Tspan15 and ADAM10 together as a single fusion protein yields a functional scissor.…”

Expression and function of transmembrane 4 superfamily proteins in digestive system cancers

“…To achieve this goal, we analyzed the expression of 33 TSPAN family proteins in 21 common tumors through the public database Oncomine, and we focused on their role in 3 common digestive tract tumors. TSPAN15 is believed to enhance tumor stemness, and it has the ability to promote tumor growth and recurrence [30]. TSPAN12 can promote tumor cell proliferation and colony formation, and high expression of CD9 is considered to be related to lymph node metastasis [31,32].…”

Expression and function of transmembrane 4 superfamily proteins in digestive system cancers

“…TSPAN15 is believed to enhance tumor stemness, and it has the ability to promote tumor growth and recurrence [20] . TSPAN12 can promote tumor cell proliferation and colony formation, and high expression of CD9 is considered to be related to lymph node metastasis [21,22] .…”