血清澱粉樣蛋白A，是一種急性期蛋白，在許多文獻中都曾發表過SAA在多種癌症中皆有出現過度表達的情形。在我們先前的研究中，我們應用基於奈米探針的親和質譜法 (NBAMS) 來識別 24 個 SAA 變異，該變異模式可已用於區分胃癌 (GC) 患者與胃病和健康個體。然而，癌症中異質SAA變異的來源仍不清楚。以往的研究認為肝臟是SAA的主要來源。然而，我們對於SAA變異模式是否具有癌症特異性感到好奇。為了探討SAA的分泌機制以其在不同癌症類型的特異性，我們分析了患者的血清、正常以及腫瘤組織以及細胞模型中的SAA變異模式，後者可能可以用於人體內SAA的分泌和修飾的模擬。本實驗透過半自動奈米探針親和進行SAA的純化，並透過基質輔助雷射脫附游離飛行時間式質譜儀 (MALDI-TOF MS) 進行分析。在血清中，SAA 變異模式在 GC 的早期和晚期癌症中表現出差異。此外，SAA模式在GC（n=186）和肝癌（HCC）（n=38）中也顯示出不同的頻率。而肝癌細胞與胃癌細胞利用細胞激素刺激進行培養。為了驗證肝癌以及胃癌患者中的SAA分泌機制，將細胞模型中的SAA變異模式與癌症患者進行比較。肝癌腫瘤組織中，SAA的變異模式與肝癌細胞一致。GC 細胞系中也未檢測到SAA，只有在與肝癌細胞共培養後才得以發現。這表明肝臟和肝外 SAA 可能是不同的。最後我們也發現了活化血清中本身的蛋白酶，會增加N端截斷的SAA，這表示血清中的蛋白酶可能導致SAA的N端截短。我們的研究揭示了胃癌 (GC) 和肝癌 (HCC) 中血清澱粉樣蛋白 A (SAA) 具有不同模式，顯示癌症特異性。我們也發現SAA的分泌和修飾受到肝臟和肝外來源的影響，血清蛋白酶也可能導致其變異的原因。

Serum amyloid A (SAA), an acute phase protein, has been reported to be overexpressed in many cancers. In our previous study, we applied nanoprobe-based affinity mass spectrometry (NBAMS) to identify 24 SAA variants, which pattern distinguished gastric cancer (GC) patients from gastric disease and healthy individuals. However, the source of the heterogeneous SAA variants in cancer is still not understood. Previous literature reported that liver is the major source to secrete SAA. However, it is intriguing if the SAA variant pattern has cancer specificity. To explore the secretion mechanism of SAA and specificity towards different cancer types, we characterized the SAA variant pattern in patient serum, paired normal and tumor tissues, and cell line models; the latter may mimic the SAA secretion and modification in human body. The SAA was purified by semi-automated nanoprobe-based affinity purification and analyzed by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). In serum, the SAA variant patterns show difference in early-stage and advanced-stage cancer in GC. In addition, the SAA pattern also shows different frequency in GC (n=185) and hepatocellular carcinoma (HCC) (N=38) Accordingly, the SAA in HCC cell lines (HepG2, Hep3B and Huh7) and GC cell lines (HGC27, N87 and AGS) simulated by inflammatory molecules (IL-6, IL-1β, TNFα). To clarify the SAA secretion mechanism in HCC and GC patients, the SAA variant patterns in cell lines were compared with the tissues in cancer patients. In HCC, the SAA variant patterns tumor tissues were consistent with the HCC cell lines. However, SAA was not detected from GC cell lines, even with cytokines treatment, and was only found after co-culture with HCC cell line;. The hepatic and extra-hepatic SAA are possibly not homologous. Lastly, activated the proteases in serum, increased N-terminal truncated SAA, which suggests that the proteases in serum likely caused the N-terminal truncation of SAA. Our study revealed distinct patterns of serum amyloid A (SAA) variants in gastric cancer (GC) and hepatocellular carcinoma (HCC), suggesting cancer-specific differences. We found that SAA secretion and modification are influenced by both hepatic and extra-hepatic sources, with serum proteases likely contributing to their variation.
Keywords: Gastrointestinal (GI) cancers / Serum amyloid A (SAA) / Variants / Isoforms/ Mass spectrometry / Cancer cell line

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