癌症轉移是導致病患死亡的主要原因，實驗室過去發現懸浮癌細胞表面纖連蛋白組裝與肺臟血管內皮細胞的CD26結合導致轉移，因此釐清此纖連蛋白組裝機制有助對抗癌症轉移。文獻指出在貼附狀態的癌細胞其STAT3的活性與纖連蛋白的表達及轉移能力均呈現正相關，然而STAT3能否藉由調控懸浮癌細胞的纖連蛋白來增加轉移能力則仍屬未知。觀察表達突變之STAT3的人類肺癌細胞AS2，發現STAT3的活性(由磷酸化705酪胺酸[pY705]之STAT3代表)的確可改變其細胞表面纖連蛋白組裝。然而，我們卻發現纖連蛋白組裝較多之高轉移癌細胞於懸浮狀態存在有一非STAT3的120 KDa較強磷酸化蛋白可被抗pY705-STAT3抗體所辨認，經質譜儀鑑定為hnRNP U，並發現其也能促進纖連蛋白組裝。除此之外，STAT3之pY705也可促進hnRNP U磷酸化。為探討hnRNP U是否參與由pY705-STAT3所調控纖連蛋白組裝的機制中，我們在可促進纖連蛋白組裝的人類肺癌細胞株AS2S3C (表達constitutively active STAT3)抑制hnRNP U表現，發現可降低其纖連蛋白組裝。接著為了解STAT3如何調控hnRNP U的磷酸化，我們首先發現S3C和S3D (表達DNA binding domain-mutated STAT3)都能促進hnRNP U磷酸化，而S3F (表達單點突變Y705F STAT3)則無此能力；另外，獨有S3C可促使hnRNP U蛋白表達增加，代表pY705-STAT3可以透過從未被報導過之非典型路徑調控hnRNP U磷酸化。文獻提到STAT3可調控癌轉移促進因子c-Met的活性，我們推測c-Met可能參與由pY705-STAT3所調控hnRNP U磷酸化的機制中。初步發現pY705-STAT3也可透過非典型路徑調控c-Met磷酸化，且抑制c-Met活性能減少hnRNP U磷酸化。文獻指出PP2A (Ser/Thr Protein phosphatase 2A；絲氨酸/蘇氨酸去磷酸酶2A)可參與癌轉移及c-Met活性的調控，我們進一步發現pY705-STAT3也的確參與調控PP2A。本篇論文提出證據指出STAT3透過調控hnRNP U進而促進懸浮癌細胞表面纖連蛋白組裝，而PP2A和c-Met很可能參與在這樣的機制當中。

The leading cause of cancer death is cancer metastasis, which could be promoted by cancer pericellular fibronectin (FN)/endothelial CD26-mediated cell-cell adhesion within lung vasculatures. Understanding the molecular mechanisms of FN assembly on suspended cancer cells may facilitate anti-metastatic strategies. It has been reported that the activity of STAT3 is intimately associated with FN expression and cancer metastasis. However, whether STAT3 regulates suspended cancer pericellular fibronectin assembly to increase metastasis remains unclear. We have previously found that STAT3 activity (represented by pY705-STAT3) promotes FN assembly on suspended cancer cell surfaces. Interestingly, there is a more obvious 120 kDa non-STAT3 protein expressed in highly FN assembled metastatic cancer cells. After mass spectrometry analysis, it is hnRNP U that is cross-reacted with the anti-pY705-STAT3 polyclonal antibody. Here we showed that suspended cancer pericellular fibronectin assembly could also be promoted by hnRNP U. Consistently, we found that pY705-STAT3 was able to promote tyrosine phosphorylation of hnRNP U. Subsequently, we knocked down hnRNP U in AS2 cancer cells ectopically expressing the constitutively activated STAT3 (STAT3-S3C) and showed that the pY705-STAT3-promoted FN assembly was decreased, suggesting that hnRNP U is indeed involved in pY705-STAT3-promoted FN assembly. Next, to further study how STAT3 regulates hnRNP U phosphorylation, we found that both STAT3-S3C and DNA-binding mutant STAT3 (STAT3-S3D) promoted hnRNP U phosphorylation but not Y705F-mutated inactive STAT3 (STAT3-S3F). On the other hand, only STAT3-S3C enhances hnRNP U protein expression. These results suggested that pY705-STAT3 may promote hnRNP U phosphorylation through a unexpected non-canonical pathway. STAT3 are known to be able to activate metastasis-promoting c-Met. Therefore, we assumed that c-Met is involved in pY705-STAT3-triggered hnRNP U phosphorylation. We showed that pY705-STAT3 was indeed capable of promoting c-Met phosphorylation through non-canonical pathway, and inhibition of c-Met activity reduced hnRNP U phosphorylation. PP2A is reported to participate in both metastasis and the regulation of c-Met activity. We also found that STAT3 promoted PP2A expression. This thesis partially unveils the molecular mechanisms of pericellular FN on metastatic cancer cells in suspension is promoted by STAT3-regulated hnRNP U, and PP2A and c-Met participate in this mechanisms.

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