Identification of Clinical Value and Biological Effects of TTN Mutation in Hepatocellular Carcinoma
Authors: Zhang Zhixue , Sun Yating , Zeng Zhirui , Li Dahuan , Cao Wenpeng , Shan Lei , Chen Tengxiang 
Published: November 2024

Abstract

Hepatocellular carcinoma (HCC) is a malignant tumor of the digestive system and one of the leading causes of cancer mortality worldwide. So far, various genetic mutations have been observed in hepatocellular carcinoma (HCC) related with tumorigenesis due to genomic instability. However, the clinical characteristic and therapeutic value of genetic mutations in HCC were extent unknown. In the present study, by analyzing the gene mutation landscape of HCC tissues from TCGA database, we demonstrated that a TTN (titin) mutation was one of the high-frequency mutations in HCC, and relevant with poor prognosis in HCC. TTN mutation had no relationship with immune signature in HCC, but linked to the change of drug sensitivity of GSK1904529A, nilotinib, 5-Fluorouracil (5-FU) and sapitinib. Furthermore, through performing the TIDE algorithm, CCK-8 assays, colony formation assays, tumor cell sphere-forming experiment, in vivo tumor transplantation experiment and relevant biological experiments to investigated the association between drug sensitivity. We found that TTN mutations led to increased stability of the TTN protein, which depletion results in a decrease in intracellular ferrous ion content, inhibiting the ferroptosis pathway, significantly reduced the sensitivity of HCC to 5-FU in vitro and in vivo. These findings demonstrated that TTN mutations cause HCC to reduce sensitivity to 5-FU, reducing treatment efficacy. In conclusion, our studies provided the initial evidences that TTN mutation can sever as biomarker for predicting the prognosis, clinical signature, molecular signature and drug sensitivity and targets for therapy of HCC. It provides a new idea for solving the drug resistance response of HCC in treatment.
Background: Hepatocellular carcinoma (HCC) is a malignant tumor of the digestive system and one of the leading causes of cancer mortality worldwide. So far, various genetic mutations have been observed in hepatocellular carcinoma (HCC) related with tumorigenesis due to genomic instability. However, the clinical characteristic and therapeutic value of genetic mutations in HCC were extent unknown.
Methods: In the present study, by analyzing the gene mutation landscape of HCC tissues from TCGA database and immune signature in HCC. Furthermore, through performing the TIDE algorithm, CCK-8 assays, colony formation assays, tumor cell sphere-forming experiment, in vivo tumor transplantation experiment and relevant biological experiments to investigated the association between drug sensitivity.
Results: The research identified TTN (titin) mutation was one of the high-frequency mutations in HCC, and relevant with poor prognosis in HCC. TTN mutation had no relationship with immune signature in HCC, but linked to the change of drug sensitivity of GSK1904529A, nilotinib, 5-Fluorouracil (5-FU) and sapitinib. And TTN mutation leads to increased stability of TTN protein, which significantly reduced the sensitivity of HCC to 5-FU in vitro and in vivo by decreasing intracellular ferrous ion levels, inhibiting the ferroptosis pathway. These findings demonstrated that TTN mutations cause HCC to reduce sensitivity to 5-FU, reducing treatment efficacy.
Conclusions: TTN mutation is one of the high frequency mutation genes in HCC, which promotes TTN protein stability, which significantly reduced the sensitivity of HCC to 5-FU in vitro and in vivo by decreasing intracellular ferrous ion levels, inhibiting the ferroptosis pathway. These findings demonstrate that TTN mutations weaken the sensitivity of HCC to 5-FU, providing a new therapeutic target to address the drug resistance response of HCC in therapy.