细胞粘附分子METCAM/MUC18表达对乳腺癌与卵巢癌细胞的体内外作用研究
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摘要
乳腺癌是女性最常见的恶性肿瘤,严重威胁着许多患者的生命。在美国,乳腺癌已成为继肺癌之后的第二大癌症死亡原因。尽管目前对乳腺癌的治疗已经取得了较大进步,但对于癌细胞已经扩散转移的患者,其生存率依然低下。因而,如何进一步提高患者的总体生存率至关重要。此外,卵巢癌亦是女性常见的恶性肿瘤之一,其发病率近年来在美国有逐年上升趋势。研究发现卵巢癌患者的预后相对较差,主要原因是多数患者被诊断发现时,癌细胞已经扩散转移或癌症已经处于晚期,因而必要寻找可靠卵巢癌细胞的预后因子或生物标记。
研究发现肿瘤生成或癌细胞转移是一个复杂的过程,涉及多方面生物学特征的改变。例如,细胞粘附分子METCAM/MUC18的异常表达常与肿瘤的发生或癌细胞的转移密切相关。已研究表明细胞粘附分子METCAM/MUC18的表达与乳腺癌的发生和/或转移具有密切的关系,但具体作用仍然不清楚。在肿瘤生成过程中是促进还是抑制肿瘤的生长目前依然没有定论,因而有必要对其进行深入地研究。此外,已研究还发现细胞粘附分子可介导卵巢癌细胞的粘附与迁移运动,但细胞粘附分子METCAM/MUC18是如何影响卵巢癌的生成及其对癌细胞迁移运动与侵袭能力的影响并不清楚,因而同样有必要进行研究。
细胞粘附分子METCAM/MUC18是一个跨膜的糖蛋白分子,属于免疫球蛋白样基因超家族,在细胞间、细胞与基质间具有重要的作用。研究发现细胞粘附分子METCAM/MUC18具有广泛的生理功能,对于维持正常的血管新生及其正常的胚胎发育至关重要。但研究还发现METCAM/MUC18的表达与色素瘤细胞的转移及前列腺癌、多种上皮瘤的生成和/或转移密切相关。然而,由于目前对细胞粘附分子METCAM/MUC18对乳腺癌与卵巢癌的作用尚不清楚,因而本文选择自身不表达与低表达METCAM/MUC18的乳腺癌细胞MCF-7与SKBR3及其选择几乎自身不表达该细胞分子的卵巢癌细胞SKOV3为研究对象,从而研究METCAM/MUC18的表达对这三种癌细胞的体内外作用。
将人METCAM/MUC18 cDAN基因通过质粒分别转染乳腺癌细胞MCF-7,SKBR3与卵巢癌细胞SKOV3,再通过G418筛选获得稳定表达该蛋白分子的克隆细胞,并对部分克隆细胞进行体外迁移运动、侵袭能力、集落形成能力及其体内致瘤性研究。其研究结果表明,通过质粒转染乳腺癌细胞与卵巢癌细胞,我们获得了稳定表达高、中与低水平METCAM/MUC18的MCF-7,SKBR3克隆细胞与SKOV3克隆细胞。研究结果发现细胞粘附分子METCAM/MUC18的表达上调可促进MCF-7与SKBR3克隆细胞的体外迁移运动,与只转染空质粒载体的对照组相比较具有显著性差异。加入抗METCAM/MUC81的抗体可降低MCF-7与SKBR3克隆细胞的体外迁移能力。此外,METCAM/MUC18的表达上调可促进MCF-7与SKBR3克隆细胞的体外侵袭能力,与对照组相比较具有显著性差异,METCAM/MUC81的抗体可降低MCF-7与SKBR3克隆细胞的体外侵袭能力。此外,我们还研究了内源性表达METCAM/MUC18的另两种乳腺癌细胞MDA-MB-231与MDA-MB-468的体外迁移运动与侵袭能力,结果发现MDA-MB-231比MDA-MB-468具有更好的体外迁移运动能力与侵袭能力;METCAM/MUC18抗体均可降低这两种细胞的体外迁移运动能力与侵袭能力。
此外,我们还发现细胞粘附分子METCAM/MUC18的表达上调同样可促进MCF-7与SKBR3克隆细胞的体外集落形成能力。这些研究结果表明乳腺癌细胞MCF-7与SKBR3的体外迁移运动、侵袭与集落形成能力的增强与METCAM/MUC18的表达有关。动物实验结果表明,转染METCAM/MUC18 cDNA基因的MCF-7可促进该克隆细胞在SCID小鼠体内的肿瘤形成或促进肿瘤在小鼠体内更早呈现。免疫组织化学染色结果表明细胞粘附分子METCAM/MUC18可在肿瘤组织特异性高表达。SKBR3克隆细胞的动物实验进一步证明了METCAM/MUC18的高表达可促进肿瘤在裸小鼠体内的形成和促进肿瘤的生长,最终的肿瘤平均重量和体积与对照组相比较具有显著性差异。接种高表达METCAM/MUC18的SKBR3克隆细胞的肿瘤组织切片染色结果可见METCAM/MUC18的特异性高表达;而对照组接种低表达METCAM/MUC18的SKBR3克隆细胞的肿瘤组织切片染色结果只见METCAM/MUC18的轻微表达且特异性极低。此外,SKBR3的三维培养结果表明高表达METCAM/MUC18的SKBR3克隆细胞比对照组具有更好的无序生长(体外致瘤性)。这些研究结果表明METCAM/MUC18的表达与乳腺癌细胞的迁移运动、侵袭、集落形成及体内致瘤性密切相关。
此外,我们研究还发现METCAM/MUC18的高表达并不促进卵巢癌细胞SKOV3的体外迁移运动,而是抑制该细胞的体外迁移运动;对该细胞的体外侵袭能力与集落形成能力的影响不明显。但是,METCAM/MUC18的表达上调不仅可抑制卵巢癌细胞SKOV3在裸小鼠体内的肿瘤或腹水生成,还可以抑制SKOV3在裸小鼠背部皮下与腹部皮下的肿瘤生成。其肿瘤切片的免疫组化染色结果表明转染METCAM/MUC18基因的SKOV3克隆细胞接种裸小鼠产生的肿瘤切片显示METCAM/MUC18特异性高表达;而对照组接种不表达METCAM/MUC18的SKOV3克隆细胞,其肿瘤切片染色结果则几乎未见METCAM/MUC18表达。这些研究结果表明细胞粘附分子METCAM/MUC18的高表达与抑制肿瘤的作用密切相关。
由此可见,METCAM/MUC18可能是一个功能复杂的细胞粘附分子,在不同肿瘤中的表达可能具有不同的作用,是促进肿瘤生长还是抑制肿瘤生长要取决于具体的癌细胞特性与特定的微环境。
Breast cancer is the most common gynecologic malignancy, which is threating many lives of patients of breast cancer. In the United States, breast cancer is the second leading cause of cancer-related death among women after lung cancer. Despite lots of advances that have been achieved in the treatment of breast cancer in recent years, the survival rate of the patients developed metastatic disease is still low. So, how to increase the survival rate of patients is very important. Besides, ovarian cancer is one of common malignant tumors, and the incidence of ovarian cancer is gradually increasing in the United State in recent years. One main reason why the prognosis of ovarian cancer remains poor is newly diagnosed patients with advanced state or metastasis. It is necessary to find specific prognosis or biomarker of ovarian cancer.
Tumorigenesis or metastasis is a complex process involving change of several biological characteristics. For example, aberrant expression of cell adhesion molecule, METCAM/MUC18 can often lead to tumorigenesis or metastasis. Although the relation between METCAM/MUC18 expression and tumorigenesis or metastasis of breast cancer was reported, the details of exact function of METCAM/MUC18 on breast cancer are not clear. Promotion or suppression of METCAM/MUC18 on breast cancer is currently controversial. Besides, cell adhesion molecules can mediate the motility and invasiveness of ovarian cancer cells, but the effects of METCAM/MUC18 expression on motility, invasion, and colony are unknown. To resolved these questions, we investigated the effects of METCAM/MUC18 expression on breast cancer cell and ovarian cancer cell in vivo and in vitro.
METCAM/MUC18 is a transmembrane cell adhesion molecule (CAM), glycoprotein, belonging to Ig-like gene super-family. It plays many important functions on cell-cell, and cell-stroma. It was reported that METCAM/MUC18 involves lots of functions to maintain the integral angiogenesis and embryo development. But it was also reported that METCAM/MUC18 expression promoted the metastasis of melanoma and promoted the tumorigenesis and metastasis of prostate cancer. Promoting tumor angiogenesis and metastasis of several epithelial tumors have been reported. However, the role of this METCAM/MUC18 in the development of breast cancer remains controversial, and the function of this protein in the development of ovarian caner remains unclear. So in order to research the effects of METCAM/MUC18 expression on breast cancer and ovarian caner, we chose two breast cancer cell lines: MCF-7, which do not express any METCAM/MUC18, and SKBR3, which express low level of this protein, and one ovarian cancer cell line, which almost did not express any of it.
We respectively transfected the human METCAM/MUC18 cDNA into breast cancer cell lines MCF-7 and SKBR3, and ovarian cancer cell SKOV3, and isolated G418-resistant clones/cells that expressed different levels of the protein. Some clones of MCF-7, SKBR3 and SKOV3 were used for testing the effects of METCAM/MUC18 on in vitro motility, invasiveness, anchorage-independent colony formation in soft agar, and in vivo tumor formation in athymic SCID mice or nude mice. Our results showed stable expression of METCAM/MUC18 in MCF-7, SKBR3 and SKOV3 clones/cells were obtained by transfection and isolation. Up-regulation of METCAM/MUC18 expression promoted in vitro motility of MCF-7 and SKBR3, and the results showed statistical difference ,comparing with vector control. The motility of the METCAM/MUC18-expressing clone was significantly reduced in the presence of anti-huMETCAM/MUC18 antibody, but not the vector clones. The up-regulation of METCAM/MUC18 promoted in vitro invasiveness of MCF-7 and SKBR3 clones/cells, and anti-huMETCAM/MUC18 antibody significantly reduced the invasion of MCF-7 and SKBR3 clones/cell expressed METCAM/MUC18. Besides, MDA-MB-231 had a significantly higher motility and invasiveness than MDA-MB-468. The motility and invasiveness of both cell lines were reduced in the presence of anti-METCAM/MUC18 antibody.
Our results showed that up-regulation of METCAM/MUC18 promoted anchorage-independent colony formation of breast cancer MCF-7,SKBR3 clones/cells. These results demonstrated METCAM/MUC18 expression can affect the motility, invasion, and colony formation in vitro. Besides, our results also showed that enforced METCAM/MUC18 expression in MCF-7 clones/cells promoted the tumor progression of human breast cancer cells MCF-7 in SCID mice or earlier presence of tumor formation. Immunohistochemistry of tumor section showed specific expression of METCAM/MUC18 of MCF-7 clones/cells. Enforced up-regulation of METCAM/MUC18 expression in SKBR3 clones/cells increased tumor proliferation and the final tumor weight and tumor volume in the nude mice showed statistical difference. The tumor sections from the mice injected with SKBR3 clones/cells expressed high level of METCAM/MUC18 demonstrated specifically high expression of METCAM/MUC18, but the tumor sections from the mice injected with vector control showed very slightly expression of METCAM/MUC18. The 3D culture of SKBR3 showed up-regulation of METCAM/MUC18 expression promoted disorganized growth than the vector control. So the results demonstrated METCAM/MUC18 express can affect the motility, invasion, colony formation in vitro, and tumorigenesis in vivo.
However, up-regulation of METCAM/MUC18 of ovarian cancer cell SKOV3 did not promoted motility of SKOV3 in vitro, and inhibited the motility of SKOV3 clones/cells, and did not affect in vitro invasiveness and anchorage-independent colony formation of SKOV3 clones/cells. But the results showed that enforced METCAM/MUC18 expression in SKOV3 clones/cells suppressed tumor formation and ascites in the nude mice. The tumor sections from the mice injected with SKOV3 clones/cells expressed high level of METCAM/MUC18 demonstrated specifically high expression of METCAM/MUC18, but the tumor sections from the mice injected with vector control showed no expression of METCAM/MUC18. These results demonstrate METCAM/MUC18 expression of SKOV3 clones/cells can affect tumorigenesis in the nude mice.
Taken together, METCAM/MUC18 probably is a complicated cell adhesion molecule and has many functions, and it probably plays different roles in different cancer cells. Promotion or suppression of tumor formation depends on specific cancer cell and special micro-environment.
研究发现肿瘤生成或癌细胞转移是一个复杂的过程,涉及多方面生物学特征的改变。例如,细胞粘附分子METCAM/MUC18的异常表达常与肿瘤的发生或癌细胞的转移密切相关。已研究表明细胞粘附分子METCAM/MUC18的表达与乳腺癌的发生和/或转移具有密切的关系,但具体作用仍然不清楚。在肿瘤生成过程中是促进还是抑制肿瘤的生长目前依然没有定论,因而有必要对其进行深入地研究。此外,已研究还发现细胞粘附分子可介导卵巢癌细胞的粘附与迁移运动,但细胞粘附分子METCAM/MUC18是如何影响卵巢癌的生成及其对癌细胞迁移运动与侵袭能力的影响并不清楚,因而同样有必要进行研究。
细胞粘附分子METCAM/MUC18是一个跨膜的糖蛋白分子,属于免疫球蛋白样基因超家族,在细胞间、细胞与基质间具有重要的作用。研究发现细胞粘附分子METCAM/MUC18具有广泛的生理功能,对于维持正常的血管新生及其正常的胚胎发育至关重要。但研究还发现METCAM/MUC18的表达与色素瘤细胞的转移及前列腺癌、多种上皮瘤的生成和/或转移密切相关。然而,由于目前对细胞粘附分子METCAM/MUC18对乳腺癌与卵巢癌的作用尚不清楚,因而本文选择自身不表达与低表达METCAM/MUC18的乳腺癌细胞MCF-7与SKBR3及其选择几乎自身不表达该细胞分子的卵巢癌细胞SKOV3为研究对象,从而研究METCAM/MUC18的表达对这三种癌细胞的体内外作用。
将人METCAM/MUC18 cDAN基因通过质粒分别转染乳腺癌细胞MCF-7,SKBR3与卵巢癌细胞SKOV3,再通过G418筛选获得稳定表达该蛋白分子的克隆细胞,并对部分克隆细胞进行体外迁移运动、侵袭能力、集落形成能力及其体内致瘤性研究。其研究结果表明,通过质粒转染乳腺癌细胞与卵巢癌细胞,我们获得了稳定表达高、中与低水平METCAM/MUC18的MCF-7,SKBR3克隆细胞与SKOV3克隆细胞。研究结果发现细胞粘附分子METCAM/MUC18的表达上调可促进MCF-7与SKBR3克隆细胞的体外迁移运动,与只转染空质粒载体的对照组相比较具有显著性差异。加入抗METCAM/MUC81的抗体可降低MCF-7与SKBR3克隆细胞的体外迁移能力。此外,METCAM/MUC18的表达上调可促进MCF-7与SKBR3克隆细胞的体外侵袭能力,与对照组相比较具有显著性差异,METCAM/MUC81的抗体可降低MCF-7与SKBR3克隆细胞的体外侵袭能力。此外,我们还研究了内源性表达METCAM/MUC18的另两种乳腺癌细胞MDA-MB-231与MDA-MB-468的体外迁移运动与侵袭能力,结果发现MDA-MB-231比MDA-MB-468具有更好的体外迁移运动能力与侵袭能力;METCAM/MUC18抗体均可降低这两种细胞的体外迁移运动能力与侵袭能力。
此外,我们还发现细胞粘附分子METCAM/MUC18的表达上调同样可促进MCF-7与SKBR3克隆细胞的体外集落形成能力。这些研究结果表明乳腺癌细胞MCF-7与SKBR3的体外迁移运动、侵袭与集落形成能力的增强与METCAM/MUC18的表达有关。动物实验结果表明,转染METCAM/MUC18 cDNA基因的MCF-7可促进该克隆细胞在SCID小鼠体内的肿瘤形成或促进肿瘤在小鼠体内更早呈现。免疫组织化学染色结果表明细胞粘附分子METCAM/MUC18可在肿瘤组织特异性高表达。SKBR3克隆细胞的动物实验进一步证明了METCAM/MUC18的高表达可促进肿瘤在裸小鼠体内的形成和促进肿瘤的生长,最终的肿瘤平均重量和体积与对照组相比较具有显著性差异。接种高表达METCAM/MUC18的SKBR3克隆细胞的肿瘤组织切片染色结果可见METCAM/MUC18的特异性高表达;而对照组接种低表达METCAM/MUC18的SKBR3克隆细胞的肿瘤组织切片染色结果只见METCAM/MUC18的轻微表达且特异性极低。此外,SKBR3的三维培养结果表明高表达METCAM/MUC18的SKBR3克隆细胞比对照组具有更好的无序生长(体外致瘤性)。这些研究结果表明METCAM/MUC18的表达与乳腺癌细胞的迁移运动、侵袭、集落形成及体内致瘤性密切相关。
此外,我们研究还发现METCAM/MUC18的高表达并不促进卵巢癌细胞SKOV3的体外迁移运动,而是抑制该细胞的体外迁移运动;对该细胞的体外侵袭能力与集落形成能力的影响不明显。但是,METCAM/MUC18的表达上调不仅可抑制卵巢癌细胞SKOV3在裸小鼠体内的肿瘤或腹水生成,还可以抑制SKOV3在裸小鼠背部皮下与腹部皮下的肿瘤生成。其肿瘤切片的免疫组化染色结果表明转染METCAM/MUC18基因的SKOV3克隆细胞接种裸小鼠产生的肿瘤切片显示METCAM/MUC18特异性高表达;而对照组接种不表达METCAM/MUC18的SKOV3克隆细胞,其肿瘤切片染色结果则几乎未见METCAM/MUC18表达。这些研究结果表明细胞粘附分子METCAM/MUC18的高表达与抑制肿瘤的作用密切相关。
由此可见,METCAM/MUC18可能是一个功能复杂的细胞粘附分子,在不同肿瘤中的表达可能具有不同的作用,是促进肿瘤生长还是抑制肿瘤生长要取决于具体的癌细胞特性与特定的微环境。
Breast cancer is the most common gynecologic malignancy, which is threating many lives of patients of breast cancer. In the United States, breast cancer is the second leading cause of cancer-related death among women after lung cancer. Despite lots of advances that have been achieved in the treatment of breast cancer in recent years, the survival rate of the patients developed metastatic disease is still low. So, how to increase the survival rate of patients is very important. Besides, ovarian cancer is one of common malignant tumors, and the incidence of ovarian cancer is gradually increasing in the United State in recent years. One main reason why the prognosis of ovarian cancer remains poor is newly diagnosed patients with advanced state or metastasis. It is necessary to find specific prognosis or biomarker of ovarian cancer.
Tumorigenesis or metastasis is a complex process involving change of several biological characteristics. For example, aberrant expression of cell adhesion molecule, METCAM/MUC18 can often lead to tumorigenesis or metastasis. Although the relation between METCAM/MUC18 expression and tumorigenesis or metastasis of breast cancer was reported, the details of exact function of METCAM/MUC18 on breast cancer are not clear. Promotion or suppression of METCAM/MUC18 on breast cancer is currently controversial. Besides, cell adhesion molecules can mediate the motility and invasiveness of ovarian cancer cells, but the effects of METCAM/MUC18 expression on motility, invasion, and colony are unknown. To resolved these questions, we investigated the effects of METCAM/MUC18 expression on breast cancer cell and ovarian cancer cell in vivo and in vitro.
METCAM/MUC18 is a transmembrane cell adhesion molecule (CAM), glycoprotein, belonging to Ig-like gene super-family. It plays many important functions on cell-cell, and cell-stroma. It was reported that METCAM/MUC18 involves lots of functions to maintain the integral angiogenesis and embryo development. But it was also reported that METCAM/MUC18 expression promoted the metastasis of melanoma and promoted the tumorigenesis and metastasis of prostate cancer. Promoting tumor angiogenesis and metastasis of several epithelial tumors have been reported. However, the role of this METCAM/MUC18 in the development of breast cancer remains controversial, and the function of this protein in the development of ovarian caner remains unclear. So in order to research the effects of METCAM/MUC18 expression on breast cancer and ovarian caner, we chose two breast cancer cell lines: MCF-7, which do not express any METCAM/MUC18, and SKBR3, which express low level of this protein, and one ovarian cancer cell line, which almost did not express any of it.
We respectively transfected the human METCAM/MUC18 cDNA into breast cancer cell lines MCF-7 and SKBR3, and ovarian cancer cell SKOV3, and isolated G418-resistant clones/cells that expressed different levels of the protein. Some clones of MCF-7, SKBR3 and SKOV3 were used for testing the effects of METCAM/MUC18 on in vitro motility, invasiveness, anchorage-independent colony formation in soft agar, and in vivo tumor formation in athymic SCID mice or nude mice. Our results showed stable expression of METCAM/MUC18 in MCF-7, SKBR3 and SKOV3 clones/cells were obtained by transfection and isolation. Up-regulation of METCAM/MUC18 expression promoted in vitro motility of MCF-7 and SKBR3, and the results showed statistical difference ,comparing with vector control. The motility of the METCAM/MUC18-expressing clone was significantly reduced in the presence of anti-huMETCAM/MUC18 antibody, but not the vector clones. The up-regulation of METCAM/MUC18 promoted in vitro invasiveness of MCF-7 and SKBR3 clones/cells, and anti-huMETCAM/MUC18 antibody significantly reduced the invasion of MCF-7 and SKBR3 clones/cell expressed METCAM/MUC18. Besides, MDA-MB-231 had a significantly higher motility and invasiveness than MDA-MB-468. The motility and invasiveness of both cell lines were reduced in the presence of anti-METCAM/MUC18 antibody.
Our results showed that up-regulation of METCAM/MUC18 promoted anchorage-independent colony formation of breast cancer MCF-7,SKBR3 clones/cells. These results demonstrated METCAM/MUC18 expression can affect the motility, invasion, and colony formation in vitro. Besides, our results also showed that enforced METCAM/MUC18 expression in MCF-7 clones/cells promoted the tumor progression of human breast cancer cells MCF-7 in SCID mice or earlier presence of tumor formation. Immunohistochemistry of tumor section showed specific expression of METCAM/MUC18 of MCF-7 clones/cells. Enforced up-regulation of METCAM/MUC18 expression in SKBR3 clones/cells increased tumor proliferation and the final tumor weight and tumor volume in the nude mice showed statistical difference. The tumor sections from the mice injected with SKBR3 clones/cells expressed high level of METCAM/MUC18 demonstrated specifically high expression of METCAM/MUC18, but the tumor sections from the mice injected with vector control showed very slightly expression of METCAM/MUC18. The 3D culture of SKBR3 showed up-regulation of METCAM/MUC18 expression promoted disorganized growth than the vector control. So the results demonstrated METCAM/MUC18 express can affect the motility, invasion, colony formation in vitro, and tumorigenesis in vivo.
However, up-regulation of METCAM/MUC18 of ovarian cancer cell SKOV3 did not promoted motility of SKOV3 in vitro, and inhibited the motility of SKOV3 clones/cells, and did not affect in vitro invasiveness and anchorage-independent colony formation of SKOV3 clones/cells. But the results showed that enforced METCAM/MUC18 expression in SKOV3 clones/cells suppressed tumor formation and ascites in the nude mice. The tumor sections from the mice injected with SKOV3 clones/cells expressed high level of METCAM/MUC18 demonstrated specifically high expression of METCAM/MUC18, but the tumor sections from the mice injected with vector control showed no expression of METCAM/MUC18. These results demonstrate METCAM/MUC18 expression of SKOV3 clones/cells can affect tumorigenesis in the nude mice.
Taken together, METCAM/MUC18 probably is a complicated cell adhesion molecule and has many functions, and it probably plays different roles in different cancer cells. Promotion or suppression of tumor formation depends on specific cancer cell and special micro-environment.
引文
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[9] Agarwal R, Kaye SB. Ovarian cancer:strategies for overcoming resistance to chemotherapy[J]. Nat Rev Cancer, 2003, 3:502-516.
[10] Lessan K, Aguiar DJ, Oegema T, et al. CD44 andβintegrin mediate ovarian carcinoma cell adhesion to peritoneal mesothelial cells [J]. Am J Pathol,1999,154:1525-1537.
[11] Jill KD, Kristen AA, Christine H, et al. Vascular cell adhesion molecule-1 is a regulator of ovarian cancer peritoneal metastasis[J]. Cancer Res, 2009,69:1469-1476.
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[17] Wu GJ. METCAM/MUC18 expression and cancer metastasis [J].Cur Genomics. 2005,6, 333-349.
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[19] Alais S, Allioli N, Pujades C, et al. HEMCAM/CD146 downregulates cell surface expression of betal integrins [J] Cell Sci, 2001, 114: 1847-1859.
[20] Okumura S, Muraoka O, Tsukamoto Y, et al. Involvement of gicerin in the extension of microvilli [J]. Exp. Cell Res , 2001, 271: 269-276.
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[24] Bowne MA, Patel DD, Li X, et al. Cloning, mapping, and characterization of activated leukocyte-cell adhesion molecule (ALCAM), a CD6 ligand [J]. J Exp Med, 1995, 181;2213-2220.
[25] Taira E, Takaha N, Taniura H, et al. Molecular cloning and functional expression of gicerin, a novel cell adhesion molecule that binds to neuite outgrowth factor [J]. Neuron, 1994, 12:861-872.
[26] Peduzzi JD, Irwin MH, Geisert EE. Distribution and characteristics of a 90kDa protein, KGCAM, in the rat CNS[J], Brain Res, 1994, 640:296-307.
[27] Vaino O, Dunon DL, Aissi F, et al. An adhesion molecule expressed by c-kit hemopoietic progenitors [J]. J Cell Biol, 1996, 135: 1655-1668.
[28] Schlagbauer WH, Jansen B, Muller, et al. Influence of MUC18/MCAM/CD146 expression on human melanoma growth and metastasis in SCID mice[J]. Int J Cancer, 1999,81:951-955.
[29] Wu GJ, Fu PP, Wang SW, et al. Enforced expression of MCAM/MUC18 increase in vitro motility and invasiveness and in vivo metastasis of two mouse melanoma K1735 Sublines in a syngeneic mouse model [J]. Mol Cancer Res, 2008,6 (11):1666-1677.
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[31] Fernanda IS, Anita T, Steven KL, et al. A subset of host B lymphocytes controls melanoma metastasis through a melanoma cell adhesion molecule/MUC18-dependent interaction:evidence from mice and humans [J]. Cancer Res, 2008,68(20):8419-8428.
[32] Jeroen WJ, Kilsdonk VR, Wilting MB, et al. Attenuation of melanoma invasion by a secreted variant of activated leukocyte cell adhesion molecule [J]. Cancer Res, 2008, 68(10):3671-3679.
[33] Kelly WH, Dorothea B. The role of N-Cadherin, MCAM andβ3 Integrin in melanoma progression , proliferation, migration and invasion [J]. Cancer biol &therapy, 2006,5:10, 1375-1382.
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