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Dysregulation of lipid metabolism is a key feature in the development and progression of hepatocellular carcinoma (HCC). Elevated expression of immunoglobulins (Ig), especially the Igκ-free light chain with a unique Vκ4-1/Jκ3 rearrangement in cancer cells, is associated with an increase in malignancy and is associated with the development of colon cancer. However, the role of Igκ in HCC carcinogenesis is unclear.
2024年10月9日，北京大学黄晶、邱晓彦共同通讯在Journal of Experimental & Clinical Cancer Research 在线发表题为“Hepatocyte-derived Igκ promotes HCC progression by stabilizing electron transfer flavoprotein subunit α to facilitate fatty acid β-oxidation”的研究论文，该研究结果表明，Igκ/ETFA轴解除了脂肪酸β-氧化的调控，促进了HCC的进展，这表明靶向脂肪酸代谢可能是一种有效的HCC治疗策略。 肝细胞源性Vκ4-1/Jκ3-Igκ可能是HCC的一个有前景的治疗靶点。
RT-PCR, Sanger sequencing, immunohistochemistry and Western blot were used to analyze the sequence and expression level of hepatocyte-derived Igκ rearrangement. Igκ in different HCC cell lines is silenced by siRNA or gRNA to assess its function in HCC tumorigenesis. To evaluate the role of Igκ in hepatocyte-specific Igκ knockout and diethyl nitrosamine (DEN) and carbon tetrachloride (CCL4)-induced mouse models of HCC in vivo. Multi-omics analysis, immunofluorescence and metabolite detection were used to study the molecular mechanism of Igκ on HCC tumorigenesis. High expression of Igκ, especially Vκ4-1/Jκ3-Igκ, was confirmed in human HCC cells. In vitro, Igκ deletion inhibits HCC cell proliferation and migration, and hepatocyte-specific Igκ deletion improves HCC progression in DEN and CCL4-induced HCC mice. Mechanistically, Vκ4-1/Jκ3-Igκ interacts with the electron-transfer flavin subunit α (ETFA) to delay its protein degradation. Loss of Igκ leads to decreased expression of mitochondrial respiratory chain complexes III and IV, leading to abnormal fatty acid β-oxidation (FAO) and lipid accumulation, thereby inhibiting the proliferation and migration of HCC cells.
Immunoglobulins (Igs) are produced by B-lineage lymphocytes and play a vital role in the immune response as antibody molecules. However, there is growing evidence that non-B cells can also widely produce immunoglobulins, which are known as non-B immunoglobulins and have different activity than antibodies, extending the functional range of immunoglobulins beyond humoral immunity. Over the past few decades, it has been demonstrated that normal non-B cells, including epithelial cells, cardiomyocytes, bone marrow cells, spermatogenic cells, and neurons, especially various epithelial tumor cells, can express Igs at high levels that promote cancer progression, metastasis, and drug resistance.
In general, B cell-derived Igs exhibit significant diversity due to Iggene rearrangements. However, tumor-derived Igs generally exhibit a lower degree of variability compared to normal B-cell-derived Igs. Previous studies have unexpectedly found that the Igκ light chain with a unique Vκ4-1/Jκ3 rearrangement pattern is widely expressed in cancer cells of different lineages, such as breast, colon, lung squamous cell carcinoma, and several other cancer cell lines. In addition, tumor cell-derived Vκ4-1/Jκ3 light chains are generally highly homogeneous, and nonpathogenic Igκ light chains are present in amyloid light chain amyloidosis (AL-AM) and light chain deposition disease (LCDD). Vκ4-1/Jκ3-Igκ has been shown to be a novel ECM protein and integrin β1 ligand; Specifically, it binds to integrin β1 and activates downstream FAK signaling to promote cancer cell proliferation and migration. High expression of Igκ is closely related to poor prognosis of breast cancer. Therefore, some studies believe that tumor-derived Igκ is closely related to the occurrence and metastasis of tumors and has pathogenic effects. Igκ expression was first found in primary hepatocytes from B-cell-deficient mice and normal hepatocyte lines, and increased hepatocyte-derived Igκ expression was found during ConA-induced liver injury. More importantly, hepatocyte-specific Igκ deletion exacerbated liver injury after ConA challenge, suggesting that hepatocyte-derived Igκ is essential for hepatocyte survival.
肝细胞来源的Igκ通过稳定ETFA促进脂肪酸β氧化来促进HCC进展（图源自Journal of Experimental & Clinical Cancer Research ）
Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for about 90% of cases, and its incidence is high in developing countries; It is the sixth most common cancer and the fourth leading cause of cancer-related death worldwide. Despite the various regimens applied in the treatment of HCC, the rate of tumor recurrence is high (50-70% within 5 years of surgery), which limits the improvement in survival; As a result, the prognosis for HCC is very bleak. In addition, drug resistance remains a major cause of targeted therapy failure. Therefore, there is an urgent need to comprehensively understand the mechanism of HCC and find new effective therapeutic targets. Metabolic reprogramming is thought to be a major marker of tumorigenesis. During carcinogenesis, cancer cells frequently reprogram metabolic pathways that control glycolysis, the tricarboxylic acid cycle (TCA), oxidative phosphorylation (OXPHOS), lipid synthesis, FAO, glutamine lysis, and mitochondrial metabolism. The important role of alterations in fatty acid metabolism in the development of hepatocellular carcinoma has been increasingly recognized. However, it is unclear whether FAO relaxation contributes to the development of HCC, and this ambiguity may be due to tumor heterogeneity. In addition, the expression of many β-oxidation-related genes varies significantly between different patients. All of the above evidence suggests that targeting FAO is a very promising strategy for the treatment of HCC.
In recent years, a series of studies have found that tumor cell-derived IgG is involved in the progression of malignant tumors, and the novel ECM protein Vκ4-1/Jκ3-Igκ is involved in the progression of colon cancer, but the role of hepatocyte-derived Igκ in HCC tumorigenesis has not been elucidated. The expression of Vκ4-1/Jκ3-Igκ in human HCC cells was confirmed, and hepatocyte-derived Igκ was confirmed to be involved in the progression of HCC. In terms of mechanism, it was found for the first time that hepatocyte-derived Vκ4-1/Jκ3-Igκ interacts with the electron transporter ETFA on the mitochondrial respiratory chain to promote lipid metabolism and cell proliferation and migration in HCC, thereby promoting the occurrence of HCC. The results of this study reveal the key role of hepatocyte-derived Igκ in the development of HCC and suggest its potential as a therapeutic target for HCC.
References:
https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-03203-8
Source: iNature