LncRNA GSTM3TV2/SOX9通路促进血管生成拟态诱导胰腺癌化疗耐药的机制研究

Understanding the mechanisms implicated in drug resistance of pancreatic cancer is critical to improving patient outcomes. Recent studies indicated that long non-coding RNA (lncRNA) may emerge as key molecules in drug resistance. However, the functional contribution of lncRNA to drug resistance in pancreatic cancer remains elusive. Our previous study demonstrated that lncRNA GSTM3TV2 was upregulated in the gemcitabine-resistant pancreatic cancer cell lines and could enhance the gemcitabine resistance of pancreatic cancer cells . Further studies indicated that GSTM3TV2 promoted cancer stem cell (CSC) properties and vasculogenic mimicry (VM) of pancreatic cancer cells. In addition, we also revealed that GSTM3TV2 could modulate the expression level of SRY-related high mobility group box 9 (SOX9), based on the data investigated by western blot and bioinformatic analysis. Therefore, we hypothesized lncRNA GSTM3TV2 could promote CSC and VM properties to enhance gemcitabine resistance in human pancreatic cancer by modulating SOX9 expression. This study will investigate the roles and mechanisms of lncRNA GSTM3TV2\SOX9 axis in regulating chemoresistance of pancreatic cancer by in vitro and in vivo. We will also evaluate clinical values of lncRNA GSTM3TV2\SOX9 in predicting prognosis of pancreatic cancer patients. No similar research is reported.

化疗耐药是导致胰腺癌患者预后差的主要原因之一。长链非编码RNA的异常调控与胰腺癌化疗耐药密切相关。课题组前期研究发现胰腺癌耐药细胞株中表达升高的lncRNA GSTM3TV2，可降低胰腺癌细胞对吉西他滨的化疗敏感性、增强胰腺癌细胞肿瘤干细胞分化特性、及诱导胰腺癌细胞血管生成拟态形成；进一步探索显示GSTM3TV2可能是通过调控胰腺癌肿瘤干细胞调节因子SOX9的表达介导上述表型。因此，我们推测：lncRNA GSTM3TV2通过促进SOX9的表达，增强胰腺癌细胞肿瘤干细胞分化特性，促进细胞血管生成拟态的形成，从而参与调控胰腺癌化疗耐药。本课题拟通过体内外实验探索lncRNA GSTM3TV2\SOX9通路对胰腺癌吉西他滨化疗敏感性的调控作用及机制；并结合临床标本，明确lncRNA GSTM3TV2\SOX9判断胰腺癌患者预后价值。经检索，国内外未见同类报道。

研究背景：化疗耐药是导致胰腺癌患者预后差的主要原因之一。长链非编码RNA对肿瘤干细胞分化、血管生成拟态的异常调控与胰腺癌化疗耐药密切相关。本课题主要探索LncRNA GSTM3TV2/SOX9通路调控肿瘤干细胞分化和血管生成拟态促进胰腺癌化疗耐药的作用和机制。.研究方法：通过体内体外实验探索LncRNA GSTM3TV2/SOX9对胰腺癌细胞化疗耐药、肿瘤干细胞分化和血管生成拟态形成的调控作用和机制；明确GSTM3TV2调控SOX9表达的机制，阐述GSTM3TV2/SOX9作为胰腺癌治疗靶点的潜在价值；同时检测人胰腺癌组织标本中GSTM3TV2表达水平，评估GSTM3TV2作为胰腺癌预后指标的临床应用价值。.研究结果：LncRNA GSTM3TV2在胰腺癌组织中表达升高；GSTM3TV2高表达是胰腺癌患者预后不良的独立危险因素。GSTM3TV2可降低胰腺癌细胞对吉西他滨的化疗敏感性，促进胰腺癌细胞增殖、迁移及侵袭和抑制细胞凋亡，并促进胰腺癌细胞的干细胞分化和血管生成拟态形成。GSTM3TV2对胰腺癌细胞化疗耐药、肿瘤干细胞分化和血管生成拟态形成的调控作用则与SOX9密切相关；抑制SOX9的表达，可降低胰腺癌细胞对吉西他滨的化疗耐药性，并抑制胰腺癌干细胞分化特性和血管生成拟态形成。进一步深入研究发现，GSTM3TV2可通过竞争性内源性RNA机制调控SOX9的表达，即通过GSTM3TV2/miR-129-5p/SOX9通路促进胰腺癌细胞SOX9的表达。.研究结论：LncRNA GSTM3TV2/SOX9通路参与调控胰腺癌化疗耐药机制与肿瘤干细胞分化、血管生成拟态形成相关，GSTM3TV2可作为胰腺癌潜在的治疗靶点和判断患者预后的肿瘤标志物。