Wang Xiao-Wei, Tang Yu-Xing, Li Fu-Xi, Wang Jia-Le, Yao Gao-Peng, Zeng Da-Tong, Tang Yu-Lu, Chi Bang-Teng, Su Qin-Yan, Huang Lin-Qing, Qin Di-Yuan, Chen Gang, Feng Zhen-Bo, He Rong-Quan
Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
Department of Pathology, Red Cross Hospital of Yulin City, Yulin 537000, Guangxi Zhuang Autonomous Region, China.
World J Gastrointest Oncol. 2024 Oct 15;16(10):4244-4263. doi: 10.4251/wjgo.v16.i10.4244.
Hepatocellular carcinoma (HCC) is a major health challenge with high incidence and poor survival rates in China. Systemic therapies, particularly tyrosine kinase inhibitors (TKIs), are the first-line treatment for advanced HCC, but resistance is common. The Rho GTPase family member Rho GTPase activating protein 12 (ARHGAP12), which regulates cell adhesion and invasion, is a potential therapeutic target for overcoming TKI resistance in HCC. However, no studies on the expression of ARHGAP12 in HCC and its role in resistance to TKIs have been reported.
To unveil the expression of ARHGAP12 in HCC, its role in TKI resistance and its potential associated pathways.
This study used single-cell RNA sequencing (scRNA-seq) to evaluate mRNA levels and explored its mechanisms through enrichment analysis. CellChat was used to investigate focal adhesion (FA) pathway regulation. We integrated bulk RNA data (RNA-seq and microarray), immunohistochemistry and proteomics to analyze mRNA and protein levels, correlating with clinical outcomes. We assessed ARHGAP12 expression in TKI-resistant HCC, integrated conventional HCC to explore its mechanism, identified intersecting FA pathway genes with scRNA-seq data and evaluated its response to TKI and immunotherapy.
mRNA was found to be highly expressed in malignant hepatocytes and to regulate FA. In malignant hepatocytes in high-score FA groups, MDK-[integrin alpha 6 (ITGA6) + integrin β-1 (ITGB1)] showed specificity in ligand-receptor interactions. ARHGAP12 mRNA and protein were upregulated in bulk RNA, immunohistochemistry and proteomics, and higher expression was associated with a worse prognosis. ARHGAP12 was also found to be a TKI resistance gene that regulated the FA pathway. ITGB1 was identified as a crossover gene in the FA pathway in both scRNA-seq and bulk RNA. High expression of ARHGAP12 was associated with adverse reactions to sorafenib, cabozantinib and regorafenib, but not to immunotherapy.
ARHGAP12 expression is elevated in HCC and TKI-resistant HCC, and its regulatory role in FA may underlie the TKI-resistant phenotype.
肝细胞癌（HCC）是一项重大的健康挑战，在中国发病率高且生存率低。全身治疗，尤其是酪氨酸激酶抑制剂（TKIs），是晚期HCC的一线治疗方法，但耐药很常见。Rho GTP酶家族成员Rho GTP酶激活蛋白12（ARHGAP12）可调节细胞黏附和侵袭，是克服HCC中TKI耐药的潜在治疗靶点。然而，尚未有关于ARHGAP12在HCC中的表达及其在TKI耐药中作用的研究报道。
揭示ARHGAP12在HCC中的表达、其在TKI耐药中的作用及其潜在相关途径。
本研究使用单细胞RNA测序（scRNA-seq）评估mRNA水平，并通过富集分析探索其机制。使用CellChat研究粘着斑（FA）途径调节。我们整合了批量RNA数据（RNA测序和微阵列）、免疫组织化学和蛋白质组学，以分析mRNA和蛋白质水平，并与临床结果相关联。我们评估了TKI耐药HCC中ARHGAP12的表达，整合了传统HCC以探索其机制，通过scRNA-seq数据鉴定FA途径的交叉基因，并评估其对TKI和免疫治疗的反应。
发现mRNA在恶性肝细胞中高表达并调节FA。在高分FA组的恶性肝细胞中，MDK-[整合素α6（ITGA6）+整合素β-１（ITGB1）]在配体-受体相互作用中表现出特异性。ARHGAP12 mRNA和蛋白在批量RNA、免疫组织化学和蛋白质组学中上调，且较高表达与较差的预后相关。还发现ARHGAP12是调节FA途径的TKI耐药基因。ITGB1在scRNA-seq和批量RNA中均被鉴定为FA途径中的交叉基因。ARHGAP12的高表达与索拉非尼、卡博替尼和瑞戈非尼的不良反应相关，但与免疫治疗无关。
ARHGAP12在HCC和TKI耐药HCC中表达升高，其在FA中的调节作用可能是TKI耐药表型的基础。
