Laminin‐γ2 overexpression in head‐and‐neck squamous cell carcinoma

Abstract

To identify molecular markers for the progression of headand-neck squamous cell carcinoma (HNSCC), we used RNA arbitrarily primed (RAP) PCR to determine the qualitative and quantitative differences in gene expression between normal epithelial cells, those derived from dysplastic oral mucosa and invasive and metastatic HNSCC. Three differentially expressed DNA fragments (RAP20, RAP21, RAP26) that were upregulated in a tumor cell line (T45) were identified as being regions of the ␥2 subunit of human laminin-5. Northern blot analysis of total cellular RNA revealed overexpression of these transcripts in 6 of 7 HNSCC cell lines compared with normal epidermal keratinocytes. In contrast, no differences were observed in HeLa (cervical carcinoma) or HCT116 (colon carcinoma) cells. Laminin is a major component of the basement membrane, which performs multiple biologic roles, including cell attachment, spreading and migration as well as being involved in cellular proliferation and differentiation. 1,2 Structurally, laminin is a heterotrimeric protein comprising ␣, ␤ and ␥ subunits, of which several variants exist. 3 Thus, different subunit combinations result in a family of laminins. 3,4 Specific biologic activities of different laminins may be reflected in the fact that these molecules show tissue-specific expression. For example, laminin-5 is considered to be an epithelial laminin as it is found as a component of basement membranes in epithelial tissues but not in mesenchyme. 5,6 Furthermore, cytokines that regulate epithelial homeostasis, such as transforming growth factor (TGF)-␤, modulate the expression of laminin-5 polypeptides in epidermal keratinocytes. 7 A role for laminin isoforms in tumor cell invasion is becoming apparent. 8 For instance, attachment of cancer cells is mediated in part by laminins. 9,10 Additionally, increased cell-surface expression of laminin was found in highly metastatic fibrosarcoma cells compared to cells of low metastatic potential. 11 Furthermore, expression and activity of matrix metalloproteases, which play critical roles in cellular invasion, are elevated in the presence of laminin, 12 and metastasis of melanoma cells is also enhanced. 13 Further studies have demonstrated that attachment and metastasis of tumor cells can be inhibited by incubation with antilaminin antibodies 14,15 or synthetic laminin peptides. 16 Several reports have implicated laminin-5 in epithelial tumor cell invasion. In one study, overexpression of the ␥2 chain of laminin-5 was found in 26 of 27 carcinomas, while various mesenchymal tumors did not express this molecule. 17 Furthermore, the highest expression of ␥2 occurred at areas of active invasion in colon adenocarcinomas, and a clear correlation was found with tumor budding. 17 In a subsequent study, these findings were extended to examine expression in a larger series of human cancers, 18 demonstrating that levels of ␥2 were indeed the highest in squamous carcinomas, particularly in cells adjacent to surrounding stromal tissue and in deeply invading cell ne...

Loss of intercellular adhesion activates a transition from low‐ to high‐grade human squamous cell carcinoma

“…36 Other types of invasive tumors, such as gastric carcinoma, 37 are known to be associated with elevated expression of g2 chain in areas of tumor cell budding, suggesting that this protein provides a migratory template to enable tumor cell invasion. The absence of staining for g2 chain at the tumor cell-stroma interface has been previously reported in poorly differentiated SCC 38 and was similar to our findings at the leading edge of invading E-cadherin-deficient tumors. In light of these findings, it appears that the diffuse and poorly organized pericellular localization of g2 chain suggests a role for laminin 5 that is distinct from its role in BM organization.…”

“…In light of these findings, it appears that the diffuse and poorly organized pericellular localization of g2 chain suggests a role for laminin 5 that is distinct from its role in BM organization. 38 Additionally, the inability to form BM appears to be an important prognostic marker whose absence is associated with a more highly aggressive form of SCC. Altered expression of the laminin 5 g2 chain is therefore a hallmark of highly invasive tumor cells that lack E-cadherin function.…”

Laminin-332-Integrin Interaction: A Target For Cancer Therapy?

“…For example, in colon carcinoma, urinary bladder carcinoma, colorectal carcinoma, SCC of the oral cavity, tongue, skin, kidney, prostate, lung, vagina, hand and neck, gastric carcinoma, alveolar carcinoma, breast cancer, splenic carcinoma, cervical adenocarcinoma, esophageal carcinoma, adenoid cystic carcinoma, ductal tumor of the pancreas, glioma, clear cell carcinoma of the ovary, and epidermoid anal cancer, cells or tissues adjacent to the tumor front express the laminin γ2 chain or its fragment [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65]. The latter fragment is also known as the laminin γ2 short arm (SA) and includes an epidermal growth factor (EGF)-like domain.…”

Cytoplasmic and stromal expression of laminin γ 2 chain correlates with infiltrative invasion in ovarian mucinous neoplasms of gastro-intestinal type

“…It is a major component of the basement membrane of various types of epithelial tissue and plays important roles in cell differentiation, adhesion, and migration (14,15 (16,17), gastric (18), intrahepatic cholangial (19), lung (20), breast (16), and pancreatic (21) adenocarcinomas, and head and neck (22), esophageal (23) and uterine cervical (16,17,24) squamous cell carcinomas and malignant melanomas (23). However, the relationship between laminin Á 2 chain expression and ovarian GI-type mucinous neoplasms, including mural nodules, has not been elucidated.…”