轉錄因子CEBPD屬於CCAAT /增強子結合蛋白家族的一員，被認為是一個有潛力的的腫瘤抑制因子，其在乳癌、血癌、子宮頸癌和肝癌中表現量皆有下降的情形。過去的研究也顯示強烈活化CEBPD可以加強癌細胞的死亡。因此，在癌細胞中活化CEBPD可以當作是治療癌症的一個策略。Sorafenib屬於酪胺酸激酶抑制劑，目前是唯一可以延長肝癌晚期患者生存期的治療藥物。然而，其功效是有限的，並且可能與遺傳異質性的原發抗藥性有關。細胞自噬為人體重要的分解代謝過程，它能將受損的胞器或蛋白質載往溶體作清除，其中小分子物質如胺基酸則可以回收再利用。研究報告分別指出肝癌細胞的自噬作用常有失活的現象，強化細胞自噬作用能引發多種癌細胞死亡，因此推論「強力活化細胞自噬作用」應可抑制肝癌形成及甚至應用於治療可能。AMPK是細胞自噬的上游活化因子。然而，過去AMPK和細胞自噬與sorafenib產生原發抗藥性的關聯仍然未知。Hep3B細胞本身對sorafenib比Huh7細胞更具抗藥性，本研究發現表皮生長因子受體（EGFR）的高活性和低細胞自噬反應，應是Hep3B細胞對sorafenib產生原發抗藥性的原因。已知糖尿病用藥metformin能透過AMPK活化CEBPD進而促進自噬細胞死亡，研究結果顯示透過metformin可以提高Hep3B細胞對sorafenib的敏感性。因此總結出活化AMPK可增進sorafenib療效及用於改善抗藥性的臨床應用。

CCAAT/Enhancer binding protein delta (CEBPD) is a transcription factor that belongs to the CCAAT/Enhancer binding protein family. CEBPD is thought to be a potent tumor suppressor, and its expression is downregulated in several cancers, including breast cancer, leukemia, cervical cancer and hepatocellular carcinoma. Strong CEBPD activation could strengthen the death of cancer cells. Therefore, activating CEBPD expression in cancer cells could be a strategy for cancer therapy. Sorafenib is currently the only treatment proven to extend the survival of patients with advanced hepatocellular carcinoma (HCC). Autophagy, a conserved intracellular degradation process, is dysregulated and involved in HCC development. Accumulated evidence suggested that AMP­activated protein kinase (AMPK) is an upstream activator of autophagy and could be suppressed in cancer cells. However, the association of AMPK and autophagy with hepatocarcinoma resistance in response to sorafenib remains less well characterized. Hep3B cells were intrinsically more resistant to sorafenib than Huh7 cells. High activity of epidermal growth factor receptor (EGFR) and low autophagic responsiveness might determine the primary resistance of Hep3B cells to sorafenib. CEBPD was responsive to metformin and promoted autophagic cell death through AMPK activation. Furthermore, metformin could improve the sensitivity of Hep3B cells to sorafenib. Taken together, metformin-induced AMPK activation should be an attractive strategy for the improvement of the efficacy of sorafenib, and help to develop personalized medicine strategies for HCC patients.

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