研究背景：腸化生(Intestinal metaplasia, IM)和解痙多肽化生(Spasmolytic polypeptide-expressing metaplasia, SPEM)被認為是胃腺癌的胃黏膜癌前病變，並且都與附基因上(epigenetic)微核糖核酸(miRNA)的調控相關。先前的研究顯示，胃癌家族親屬在幽門螺旋桿菌感染後易出現胃黏膜癌前病變。我們首先(I)探討高胃癌風險之胃癌親屬之解痙多肽化生之患病率和分佈，並與低風險之非潰瘍性消化不良病患對照相比，探討幽門螺桿菌除菌後解痙多肽化生的可逆性。(II)接著並進一步研究血液中胃蛋白酶原和三葉因子家族蛋白(trefoil factor family, TFF)是否可用於檢測組織學上的癌前病變。最後(III)我們將評估幽門螺旋桿菌感染相關之微核糖核酸與腫瘤抑制基因調控網絡於腸化生上的影響。
研究方法：我們前瞻性招募了年齡和性別相符之高風險胃癌親屬與非潰瘍性消化不良病患作為對照，病患將接受上消化道內視鏡檢查以確定胃組織學和胃粘膜幽門螺旋桿菌狀態。透過酵素結合免疫吸附分析法(ELISA)檢測血清中胃蛋白酶原和三葉因子家族蛋白濃度與胃粘膜組織學上癌前病變表現的相關性。並基於整合微核糖核酸的和相關之下游基因數據分析，檢測可能的微核糖核酸及相關下游調控基因於胃腸化生之調節網絡。
結果：高風險胃癌親屬罹患解痙多肽化生癌前病變的機會高於非潰瘍性消化不良病患（42% vs. 14%，P < 0.01）。根除幽門螺旋桿菌感染可使胃黏膜組織學達到70.7％的解痙多肽化生癌前病變消退。血清中胃蛋白酶原和三葉因子蛋白濃度並無法預測胃粘膜組織學上之癌前病變。當病患胃組織學上具有胃體炎性指數(corpus gastritis index, CGI)陽性時、血清中三葉因子蛋白濃度與胃組織學上解痙多肽化生癌前病變的嚴重度相關 (P = 0.032）。對於胃體炎性指數陰性的病患，血清中三葉因子蛋白濃度與胃幽門螺旋桿菌感染之菌量及胃竇發炎程度相關（P = 0.001）。
對於調控胃部腸化生表現之相關微核糖核酸與下游調控基因之調節網絡，我們首先探討幽門螺旋桿菌感染相關的微核糖核酸（miR-21，miR-155，miR-223）和腫瘤抑制因子MDGA2 (MAM domain containing glycosylphosphatidylinositol anchor 2, MDGA2)調控網絡在腸化生的調控。幽門桿菌感染導致MKN1細胞抑癌基因MDGA2的表現下降，且與菌落量及時間長短相關。在幽門桿菌感染的胃粘膜上皮組織、隨著感染所造成胃炎至胃癌前組織學上病理變化、也伴隨抑癌基因MDGA2表現的逐步下降。AGS細胞外加MDGA2表現、會減少腸化生標記CDX2及TFF2表現。此外隨著感染所造成胃炎至胃癌前病理組織學改變外、也伴隨MDGA2抑癌基因相關微型核糖核酸的表現。根除幽門螺旋桿菌可使具有解痙多肽化生癌前病變的病患、胃組織黏膜微型核糖核酸的表現下降與相對應之MDGA2表現上升、但與胃組織黏膜不具癌前病變之病患相比、變化的程度並沒有完全可逆。
結論：幽門螺旋桿菌感染的胃癌親屬於幽門桿菌感染後易出現解痙多肽化生之胃癌前病變，驗證了胃癌前病變的家族性聚集。腫瘤抑制因子的潛在相互作用及其通過微核糖核酸的協調調節，代表了微核糖核酸網絡在腸化生的發展中的影響。幽門螺旋桿菌感染的根除不能完全改善胃癌前病變組織學在胃黏膜上的微型核糖核酸的表現。長期幽門螺旋桿菌的感染可能誘導胃黏膜基因的表觀遺傳修飾，但無法由幽門螺旋桿菌除菌而逆轉。

Background and Aim: Intestinal metaplasia (IM) and spasmolytic polypeptide-expressing metaplasia (SPEM) are considered neoplastic precursors of gastric adenocarcinoma and are both related to the epigenetic regulation of microRNA (miRNA) expression. Previous studies have found that the gastric cancer family (GCF) first relatives tend to present with gastric pre-neoplastic lesions after H. pylori infection. Firstly, (I) we first aimed to explore the prevalence and distribution of SPEM in first degree relatives of GCF and the reversibility of SPEM after H. pylori eradication, in comparison with a control group of patients diagnosed with non-ulcer dyspepsia (NUD). (II) Secondly, to investigate if serum levels of pepsinogen I/II and trefoil factor family (TFF) proteins were useful for detecting gastric metaplasia. Finally, (III) we intended to evaluate the potential roles of the miRNAs mediating genetic network involved in the regulation of gastric metaplasia.
Methods: In our prospective study, two subject groups, experimental group of GCFs and control NUD patients, were matched according to age and gender and given a panendoscopy to determine their gastric histology and H. pylori status. Serum levels of TFF2, TFF3, and pepsinogen I/II were checked by means of the enzyme-linked immunosorbent assay (ELISA). The quantitative reverse transcription-PCR method was used both to perform an integrated analysis of miRNA and mRNA data related to human precancerous lesions and to derive bioinformatic predictions in order to identify possible miRNA-mRNA regulatory networks. MDGA2 was overexpressed in Gastric cancer cell lines to evaluate its effects on the expression of metaplasia markers. Finally, the expression of miRNAs in response to pre-neoplastic precursors was examined both before and after H. pylori eradication.
Results: GCF subjects exhibited a higher prevalence of SPEM than NUD controls did (42% vs 14%, P < 0.01). The eradication of H. pylori achieved a 70.7% regression of SPEM. Serum levels of neither TFF nor pepsinogen predicted the presence of histologic SPEM or IM. Serum levels of TFF2 were higher in GCFs with the corpus-predominant gastritis index (CGI) who also had advanced SPEM (P = 0.032) than those of control subjects. For GCFs without the CGI, elevated serum levels of TFF2 correlated with a higher H. pylori density and more severe antral gastritis (P = 0.001).
Regarding miRNA-mRNA regulatory networks, the miRNA‐21/155/223 and MDGA2 circuit involved in the development of gastric metaplasia. In the case of these regulatory network, infection with the H. pylori strain (Hp1033) downregulated the expression of MDGA2 in a dose- and time-dependent manner in gastric cell lines (P > 0.05). The gradually declining levels of MDGA2 correspond to progressive changes in the degree of severity, from inflammatory status to advanced stage of gastric metaplasia, and cancer, which is reminiscent of Correa cascade. The expression of miRNA‐21, ‐155, and ‐223 in the antral mucosa was significantly higher in subjects with SPEM and IM, respectively, than in those without such pre-neoplastic lesions. Surprisingly, TFF2, marker for SPEM and IM marker, CDX2, critical transcription factors and intestinal patterning, were downregulated following the overexpression of MDGA2 in gastric cell lines. Alterations in the reciprocal expression patterns of MDGA2 and miR‐21, 155, and 223 were partially reversible after the eradication of H. pylori from the SPEM lineages, but this was not achieved as completely as compared with non-neoplastic lesions (Helicobacter-induced gastritis).
Conclusions: The H. pylori-infected GCF subjects were prone to SPEM, which indicates familial clustering of gastric pre-neoplastic lesions. The potential interplay between tumor suppressors and their coordinated regulation by miRNAs suggests that a miRNA network may be responsible for the expression of intestinal transcripts during the development of metaplasia. The eradication of H. pylori did not totally achieve the histological regression of SPEM, nor did it completely mitigate miRNA dysregulation in subjects with SPEM. Chronic colonization by H. pylori might induce an epigenetic modification in the gastric mucosal genes, which could not be completely reversible by means of bacterial eradication alone.

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