人類乳鐵蛋白/人類血清白蛋白融合蛋白透過破壞癌細胞高爾基體pH恆定性，強力抑制與癌細胞轉移相關的細胞遷移
闡明hLF-HSA融合蛋白抑制癌細胞遷移的機制。
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東京工科大學（東京都八王子市，校長：香川豐）大學院生物資訊傳媒研究科的Nopia Hana（博士班學生）、木村將大助教、栗本大輔（博士班畢業生）及佐藤淳教授等人的研究團隊發現，人類乳鐵蛋白（以下簡稱hLF，註1）與人類血清白蛋白（以下簡稱HSA）的融合蛋白（hLF-HSA），能透過促進高爾基體（註2）上表現的Na+/H+交換輸送體7（NHE7）（註3）的表現，進而導致其鹼化，並引發細胞內攝取訊號的網格蛋白依賴性內吞作用訊號，從而強力抑制與癌細胞轉移密切相關的遷移（細胞移動）。此發現預期能導向新的藥物開發策略。本研究成果已於2026年3月24日刊載於歐洲生化學會聯合會（FEBS）的國際科學期刊「FEBS Open Bio」。利用hLF開發生物醫藥品，目前正由生物創投公司S&K Biopharma Co., Ltd.（註4）進行中。
【研究背景】
癌症轉移是影響患者預後的重大臨床課題，而癌細胞的遷移（細胞移動）是轉移中的重要步驟。基質金屬蛋白酶1（MMP1）是一種分解細胞外基質的酵素，在癌細胞遷移中扮演重要角色。該團隊的先前研究曾報告，hLF-HSA處理能降低人類肺腺癌細胞株PC-14中MMP1的表現，進而抑制其遷移（文獻1）。本研究釐清，hLF-HSA處理導致MMP1表現下降的原因，是透過促進細胞內小器官（高爾基體）上表現的NHE7表現，進而破壞高爾基體的pH恆定性（功能受損），以及在hLF-HSA細胞內攝取時活化的網格蛋白依賴性內吞作用訊號所致。
【社會與學術重點】
高爾基體在細胞遷移中扮演極為重要的角色，因此，透過破壞高爾基體的pH恆定性來使其功能失調，預期能有效抑制癌細胞遷移。本研究中，hLF-HSA透過促進高爾基體上表現的NHE7表現，破壞了高爾基體的pH恆定性並導致其功能失調。此功能失調降低了在癌細胞遷移中扮演重要角色的MMP1的表現，進而抑制了遷移。此外，研究也發現，在hLF-HSA細胞內攝取時活化的網格蛋白依賴性內吞作用訊號，能獨立於上述對NHE7的影響，導致MMP1表現下降。透過這兩種機制，hLF-HSA能強力抑制癌細胞的遷移。
考量到高爾基體在正常細胞中的功能，hLF-HSA可能對正常細胞產生副作用。然而，研究已明確指出，hLF-HSA能選擇性地抑制癌細胞的增殖，而對正常細胞的增殖沒有影響（文獻2）。因此，本研究的hLF-HSA作為一個研究範例，證明了以破壞高爾基體功能為主要作用機制的癌細胞遷移抑制藥物開發概念的有效性，值得關注。
【論文資訊】
論文名稱：Suppression of lung adenocarcinoma migration through organelle alkalization by human lactoferrin – albumin fusion
作者：Hana Nopia, Masahiro Kimura, Daisuke Kurimoto &
常見問題
What is the main finding of this research?
The research found that a fusion protein called hLF-HSA can strongly inhibit cancer cell migration, a key step in metastasis, by disrupting the pH balance within the cancer cells' Golgi bodies.
How does hLF-HSA inhibit cancer cell migration?
hLF-HSA works through two main mechanisms: 1. It promotes the expression of NHE7 in the Golgi body, leading to its alkalinization and functional impairment, which reduces MMP1 expression. 2. It activates caveolin-dependent endocytosis signals during its uptake into the cell, which also leads to a reduction in MMP1 expression, independently of the Golgi body effect.
What is the significance of targeting the Golgi body's pH homeostasis?
The Golgi body is crucial for cell migration. Disrupting its pH homeostasis and impairing its function is a novel strategy to inhibit cancer cell migration. This research demonstrates the effectiveness of this approach.
Does hLF-HSA affect normal cells?
While the Golgi body is important in normal cells, studies have shown that hLF-HSA selectively inhibits cancer cell proliferation without affecting normal cell proliferation, suggesting a potential for targeted cancer therapy with fewer side effects.
What is the potential application of this research?
This research is expected to lead to the development of new drug discovery strategies for cancer metastasis, potentially leading to novel therapeutic agents that target the Golgi body's function.
Where was this research published?
The research was published in the international scientific journal 'FEBS Open Bio' by the Federation of European Biochemical Societies (FEBS).
Is hLF-HSA already available as a drug?
The development of biopharmaceuticals using hLF is being advanced by the bio-venture company S&K Biopharma Co., Ltd., but it is not yet available as a drug. This research provides a basis for further development.
What is MMP1 and why is its reduction important?
MMP1 (Matrix metalloproteinase 1) is an enzyme that breaks down the extracellular matrix. Reducing MMP1 expression is important because it hinders cancer cells' ability to migrate and invade surrounding tissues, thus inhibiting metastasis.
What is NHE7?
NHE7 (Na+/H+ exchanger 7) is a transporter protein expressed in the Golgi body that plays a role in maintaining its pH balance. The research found that hLF-HSA promotes the expression of NHE7.
What is caveolin-dependent endocytosis?
It is a process by which cells internalize substances from outside the cell, involving a protein called caveolin. This mechanism was found to be activated during the uptake of hLF-HSA and contributes to the inhibition of cancer cell migration.