Computational Recognition and Clinical Verification of TGF-β-Derived miRNA Signature With Potential Implications in Prognosis and Immunotherapy of Intrahepatic Cholangiocarcinoma

Zaoqu Liu; Siyuan Weng; Hui Xu; Libo Wang; Long Liu; Yuyuan Zhang; ChunGuang Guo; Qin Dang; Zhe Xing; Taoyuan Lu; Xinwei Han

doi:10.3389/fonc.2021.757919

Computational Recognition and Clinical Verification of TGF-β-Derived miRNA Signature With Potential Implications in Prognosis and Immunotherapy of Intrahepatic Cholangiocarcinoma

Front Oncol. 2021 Oct 25:11:757919. doi: 10.3389/fonc.2021.757919. eCollection 2021.

Authors

Zaoqu Liu^{1

2

3}, Siyuan Weng^{1

2

3}, Hui Xu^{1

2

3}, Libo Wang⁴, Long Liu⁴, Yuyuan Zhang¹, ChunGuang Guo⁵, Qin Dang⁶, Zhe Xing⁷, Taoyuan Lu⁸, Xinwei Han^{1

2

3}

Affiliations

¹ Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Interventional Institute of Zhengzhou University, Zhengzhou, China.
³ Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China.
⁴ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁵ Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁶ Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁷ Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁸ Department of Cerebrovascular Disease, Zhengzhou University People's Hospital, Zhengzhou, China.

Abstract

MicroRNAs (miRNAs) were recently implicated in modifying the transforming growth factor β (TGF-β) signaling in multiple cancers. However, TGF-β-derived miRNAs and their potential clinical significance remain largely unexplored in intrahepatic cholangiocarcinoma (ICC). In this study, we proposed an integrated framework that enables the identification of TGF-β-derived miRNAs in ICC (termed "TGFmitor"). A total of 36 TGF-β-derived miRNAs were identified, of which nine significantly correlated with overall survival (OS) and aberrantly expressed in ICC. According to these miRNAs, we discovered and validated a TGF-β associated miRNA signature (TAMIS) in GSE53870 (n =63) and TCGA-CHOL (n =32). To further confirm the clinical interpretation of TAMIS, another validation based on qRT-PCR results from 181 ICC tissues was performed. TAMIS was proven to be an independent risk indicator for both OS and relapse-free survival (RFS). TAMIS also displayed robust performance in three cohorts, with satisfactory AUCs and C-index. Besides, patients with low TAMIS were characterized by superior levels of CD8+ T cells infiltration and PD-L1 expression, while patients with high TAMIS possessed enhanced CMTM6 expression. Kaplan-Meier analysis suggested CMTM6 could further stratify TAMIS. The TAMIS^highCMTM6^high subtype had the worst prognosis and lowest levels of CD8A and PD-L1 expression relative to the other subtypes, indicating this subtype might behave as "super-cold" tumors. Notably, the improved discrimination was observed when CMTM6 was combined with TAMIS. Overall, our signature could serve as a powerful tool to help improve prognostic management and immunotherapies of ICC patients.

Keywords: TGF-β; immunotherapy; intrahepatic cholangiocarcinoma; microRNAs; prognosis; recurrence.