Hnrnpc, also known as heterogeneous nuclear ribonucleoprotein C (C1/C2), is an essential and ubiquitously abundant protein involved in mRNA processing. It participates in nucleic acid metabolism and has been linked to multiple biological processes [1,2]. Dysregulation of Hnrnpc has been associated with various diseases, including cancer and neurodevelopmental disorders [1,2].

In cancer, Hnrnpc plays significant roles. In hepatocellular carcinoma (HCC), its downregulation inhibits IL-6/STAT3-mediated metastasis by decreasing HIF1A expression, and patients with positive Hnrnpc expression have decreased overall survival and increased recurrence rate [1]. In clear cell renal cell carcinoma, circPPAP2B promotes metastasis via Hnrnpc-dependent alternative splicing [3]. In cervical cancer, Hnrnpc mediates lymphatic metastasis through m6A-dependent alternative splicing of FOXM1 [4]. In papillary thyroid carcinoma, Hnrnpc modulates PKM alternative splicing via m6A methylation to promote aerobic glycolysis and drive malignant progression [5]. In breast cancer, Hnrnpc promotes collagen fiber alignment and immune evasion via activation of the VIRMA-mediated TFAP2A/DDR1 axis [6]. In autoimmune thyroid disease, targeting Hnrnpc suppresses thyroid follicular epithelial cell apoptosis and necroptosis through m6A-modified ATF4 [7]. In addition, Hnrnpc haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder [2].

In conclusion, Hnrnpc is crucial in mRNA processing and nucleic acid metabolism. Its dysregulation is associated with various cancers and a neurodevelopmental disorder. Studies, especially those using loss-of-function models in different disease contexts, have revealed its diverse roles in promoting tumor metastasis, regulating cell metabolism, and affecting alternative splicing related to disease-associated genes. This understanding provides potential targets for diagnosis, prognosis, and treatment in these diseases.

References:

1. Liu, Danfei, Luo, Xiangyuan, Xie, Meng, Huang, Wenjie, Xia, Limin. 2022. HNRNPC downregulation inhibits IL-6/STAT3-mediated HCC metastasis by decreasing HIF1A expression. In Cancer science, 113, 3347-3361. doi:10.1111/cas.15494. https://pubmed.ncbi.nlm.nih.gov/35848884/

2. Niggl, Eva, Bouman, Arjan, Briere, Lauren C, Elgersma, Ype, van Esbroeck, Annelot C M. . HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder. In American journal of human genetics, 110, 1414-1435. doi:10.1016/j.ajhg.2023.07.005. https://pubmed.ncbi.nlm.nih.gov/37541189/

3. Zheng, Zaosong, Zeng, Xiangbo, Zhu, Yuanchao, Li, Fei, Tan, Wanlong. 2024. CircPPAP2B controls metastasis of clear cell renal cell carcinoma via HNRNPC-dependent alternative splicing and targeting the miR-182-5p/CYP1B1 axis. In Molecular cancer, 23, 4. doi:10.1186/s12943-023-01912-w. https://pubmed.ncbi.nlm.nih.gov/38184608/

4. Liu, Yun-Yun, Xia, Meng, Chen, Zhi-Bo, Lu, Huai-Wu, Yao, Shu-Zhong. 2024. HNRNPC mediates lymphatic metastasis of cervical cancer through m6A-dependent alternative splicing of FOXM1. In Cell death & disease, 15, 732. doi:10.1038/s41419-024-07108-4. https://pubmed.ncbi.nlm.nih.gov/39375330/

5. Rong, Shikuo, Dai, Bao, Yang, Chunrong, Chen, Jian, Wu, Zeyu. 2024. HNRNPC modulates PKM alternative splicing via m6A methylation, upregulating PKM2 expression to promote aerobic glycolysis in papillary thyroid carcinoma and drive malignant progression. In Journal of translational medicine, 22, 914. doi:10.1186/s12967-024-05668-9. https://pubmed.ncbi.nlm.nih.gov/39380010/

6. Lian, Bin, Yan, Shuxun, Li, Jiayi, Bai, Zhengyang, Li, Jinping. 2023. HNRNPC promotes collagen fiber alignment and immune evasion in breast cancer via activation of the VIRMA-mediated TFAP2A/DDR1 axis. In Molecular medicine (Cambridge, Mass.), 29, 103. doi:10.1186/s10020-023-00696-5. https://pubmed.ncbi.nlm.nih.gov/37528369/

7. Mo, Ke, Chu, Yongli, Liu, Yang, Song, Xicheng, Zhou, Jin. 2023. Targeting hnRNPC suppresses thyroid follicular epithelial cell apoptosis and necroptosis through m6A-modified ATF4 in autoimmune thyroid disease. In Pharmacological research, 196, 106933. doi:10.1016/j.phrs.2023.106933. https://pubmed.ncbi.nlm.nih.gov/37729957/