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

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

doi:10.3389/fonc.2021.757919

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 TAMIShighCMTM6high 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.

Highlights

Intrahepatic cholangiocarcinoma (ICC) is a primary malignant tumor with high heterogeneity and invasiveness, mainly originating from the secondary bile duct [1]
This suggested that cholesterol and phospholipid metabolisms were weakened, while proliferation and transforming growth factor b (TGF-b) were enhanced in intrahepatic cholangiocarcinoma (ICC)
We introduced an integrated framework that enables the identification of TGF-b-derived miRNAs in ICC

Summary

Introduction

Intrahepatic cholangiocarcinoma (ICC) is a primary malignant tumor with high heterogeneity and invasiveness, mainly originating from the secondary bile duct [1]. Over the past few decades, the incidence of ICC has increased by up to 10-fold globally [1,2,3]. Given the unfavorable prognosis of ICC, mortality should parallel incidence rates [1]. Surgical resection remains the mainstay of latently curative treatment for ICC, with median relapse-free survival (RFS) durations of 1-3 years [4, 5]. Immunotherapies that function by targeting immune checkpoints have achieved encouraging progression in cancer treatment [6]. To date, only a subset of patients yields considerable benefit in ICC [7]. Early intervention for the “high-risk” ICC is vital to improve clinical outcomes of patients and searching for new ways to stratify ICC patients is imperative

Methods

Results

Conclusion