Abetamann V, Kern H F, Elsässer H P
Department of Cell Biology and Cell Pathology, University of Marburg, Robert-Koch-Strasse 5, D-35033 Marburg, Germany.
Clin Cancer Res. 1996 Sep;2(9):1607-18.
To explore the putative role of hyaluronan (HA) in tumor invasion in pancreatic cancer, we investigated the expression of the HA receptors CD44s and RHAMM in a panel of human pancreatic cancer cell lines. Expression of CD44s has been found in only 1 of 10 cell lines included in this study. This cell line exhibits a highly differentiated phenotype without any metastatic potential when injected into nude mice. Since it has previously been shown that normal pancreatic duct cells express a high level of CD44s, our results indicate that pancreatic cancer may be accompanied by an almost complete loss of CD44s expression. As demonstrated by PCR amplification, this loss of CD44s expression is due to alternative splicing of CD44 pre-RNA. Although most of the pancreatic cancer cell lines express a complex but identical pattern of variant CD44 gene transcripts, only one higher molecular weight CD44 isoform can be detected in a subset of pancreatic cancer cell lines in Western blot analysis. This variant CD44 molecule represents the epithelial CD44 isoform (CD44v8-v10). When cells are cultured on Matrigel, the expression of additional CD44 variants is induced, suggesting that the extracellular matrix can influence the expression of CD44 isoforms and thereby may facilitate tumor invasion. This induction could be due to a regulatory process in the translation of the CD44 variant mRNAs expressed in pancreatic tumor cells. Molecular cloning of a cDNA encoding human RHAMM reveals that both HA receptors are structurally unrelated. In addition, they share an inverse expression pattern. RHAMM mRNA is overexpressed in pancreatic cancer cell lines exhibiting a poorly differentiated phenotype and a high metastatic potential when injected into nude mice. These results indicate that CD44 and RHAMM differentially contribute to invasion of pancreatic adenocarcinoma; however, these functions still remain to be determined.
为了探究透明质酸（HA）在胰腺癌肿瘤侵袭中的假定作用，我们研究了一组人胰腺癌细胞系中HA受体CD44s和RHAMM的表达情况。在本研究纳入的10个细胞系中，仅在1个细胞系中发现了CD44s的表达。将该细胞系注射到裸鼠体内时，它表现出高度分化的表型且无任何转移潜能。由于先前已表明正常胰腺导管细胞表达高水平的CD44s，我们的结果表明胰腺癌可能伴随着CD44s表达几乎完全丧失。如通过PCR扩增所证明的，CD44s表达的丧失是由于CD44前体RNA的可变剪接。尽管大多数胰腺癌细胞系表达复杂但相同模式的可变CD44基因转录本，但在蛋白质印迹分析中，仅在一部分胰腺癌细胞系中可检测到一种分子量更高的CD44异构体。这种可变CD44分子代表上皮CD44异构体（CD44v8-v10）。当细胞在基质胶上培养时，会诱导额外的CD44变体表达，这表明细胞外基质可影响CD44异构体的表达，从而可能促进肿瘤侵袭。这种诱导可能是由于胰腺肿瘤细胞中表达的CD44可变mRNA翻译过程中的调节机制。编码人RHAMM的cDNA的分子克隆表明，这两种HA受体在结构上不相关。此外，它们呈现相反的表达模式。RHAMM mRNA在注射到裸鼠体内时表现出低分化表型和高转移潜能的胰腺癌细胞系中过表达。这些结果表明，CD44和RHAMM对胰腺腺癌的侵袭有不同作用；然而，这些功能仍有待确定。
