高等級的神經內分泌肺癌由小細胞肺癌(SCLC)與大細胞神經內分泌癌所組成(LCNEC)，兩者皆有高侵襲力與不良的預後。而從肺腺癌變成SCLC或LCNEC的轉化現象，也發生在產生對表皮生長因子受體酪胺酸激酶抑制劑(EGFR-TKI)的抗藥性的過程中。此外，在神經內分泌肺癌的治療中，即使一開始對化療藥物有反應，最後仍不可避免地產生對化療的抗藥性。因此，辨別出新穎的治療標的成為治療神經內分泌肺癌的迫切需求。這篇研究中，我們指出一個主要表現在神經發育中的分子VGF，其在SCLC、LCNEC，以及一個肺腺癌子群中有高度表現。抑制VGF可降低癌細胞的生長與腫瘤的生成，而在較晚期的SCLC，以及存活狀況較差的肺腺癌病患中也發現較高的VGF表達。此外，在經EGFR-TKI處理而篩選出對EGFR-TKI有抗藥性的肺腺癌中，也有VGF表現的上升。且VGF受到表觀遺傳的調控，VGF帶有HDAC1結合的位點，而HDAC1的抑制在肺腺癌中會促進VGF的表現。另外，VGF與化療抗藥性的產生有明顯關聯，抑制VGF會誘導促細胞凋亡因子BMF與BCL2L11的表現，並且讓肺癌細胞對化療藥物較為敏感。這些結果指出VGF在具有神經內分泌特徵的肺癌中，有作為預後標記與治療靶點之潛力。

High-grade neuroendocrine tumors (NETs) of the lung comprise small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). Both exhibit aggressive malignancy with poor prognosis. The transformation toward SCLC or LCNEC from lung adenocarcinoma (ADC) also contributes to the obtain of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Despite the initial response to chemotherapy agents, patients with high-grade NET inevitably develop chemoresistance; thus, identifying novel therapeutic targets is an urgent need for these patients. This study revealed that VGF (nerve growth factor inducible), a factor majorly expressed in neurons during neural development, is enriched in SCLC and LCNEC as well as in a subgroup of lung ADCs, whereas targeting VGF reduces cancer cell growth and in vivo tumorigenesis. High VGF expression was correlated with advanced SCLC stage and predicted poor survival outcome in lung ADC. Additionally, EGFR-TKI selection enhanced VGF expression in TKI-resistant lung ADC under epigenetic control. The VGF locus possessed the HDAC1 binding site, and HDAC1 inhibition induced VGF expression in lung ADC cells. High VGF expression was associated with chemoresistance, and VGF silencing promoted expression of proapoptotic factor BMF and BCL2L11. Moreover, silencing VGF endowed lung cancer cells with sensitivity to chemotherapy drugs. These results indicate the potential of VGF as a prognostic marker and therapeutic target in lung cancers with neuroendocrine feature.

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