Knockdown of terminal differentiation induced ncRNA (TINCR) suppresses proliferation and invasion in hepatocellular carcinoma by targeting the miR‐218‐5p/DEAD‐box helicase 5 (DDX5) axis

Abstract

Terminal differentiation induced ncRNA (TINCR), a newly identified lncRNA, has been found to be associated with different human cancers including hepatocellular carcinoma (HCC). However, little is known regarding the pathological mechanisms of TINCR in HCC progression. In this study, we confirmed that TINCR expression was upregulated in HCC tumors and cell lines, and high TINCR expression was associated with larger tumor size, advanced tumor node metastasis stage, and poor prognosis. Functionally, knockdown of TINCR facilitated apoptosis and suppressed viability, colony formation and invasion in Huh7 and Hep3B cells. Mechanically, TINCR functioned as competing endogenous RNA (ceRNA) to regulate DEAD-box helicase 5 (DDX5) expression through sponging miR-218-5p. Moreover, the miR-218-5p expression was downregulated and DDX5 expression was upregulated in HCC tumors. The silencing of miR-218-5p or ectopic expression of DDX5 abated the tumor-suppressive effect of TINCR knockdown in vitro.Furthermore, si-TINCR-induced inactivation of AKT signaling was rescued by suppression of miR-218-5p or overexpression of DDX5. Also, the silencing of TINCR resulted in tumor growth inhibition in vivo. In summary, knockdown of TINCR suppressed HCC progression presumably by inactivation of AKT signaling through targeting the miR-218-5p/DDX5 axis, suggesting a novel TINCR/miR-218-5p/DDX5 pathway and therapy target for HCC.

TINCR: An lncRNA with dual functions in the carcinogenesis process

“…In HCC, two distinct studies showed association between over-expression of this lncRNA and induction of apoptosis via regulation of P53 and enhancement of cell proliferation via modulation of the miR-214-5p/ROCK1 axis, respectively [ 16 , 17 ]. Consistent with the latter study, depletion of this lncRNA in other HCC cell liens decreased oncogenic behavior through modulation of miR‐218‐5p/DDX5/AKT signaling [ 18 ].…”

“…Notably, Kaplan-Meier analyses have shown correlation between expression levels of this lncRNA and patients survival in both directions. This issue has been reported in patients with lung cancer [ 14 , 15 ] and HCC [ 18 , 30 ]. Table 3 summarizes the results of studies which reported aberrant expression of TINCR in clinical samples.…”

“…For instance, in gastric tissues, it exerts a competing endogenous RNA (ceRNA) role to modulate PDK1 expression by sponging miR-375 [ 4 ]. In colorectal and hepatic tissues, TINCR has been shown to exert its effects through sponging miR-7-5p and miR-214-5p, respectively [ 12 , 18 ]. Finally, in lung tissues, it regulates cell proliferation through sponging miR-29b [ 28 ].…”

“… – – [ 16 ] 60 pairs of HCC tissues and normal adjacent tissues Up – – – [ 18 ] 56 pairs of HCC tumor tissues and adjacent normal liver tissues Up High TINCR expression was correlated with worse OS. – – [ 18 ] Glioma 61 pairs of glioma tissues and normal adjacent tissues Down – – – [ 25 ] Breast cancer 26 GEO datasets with 4140 breast cancer including patients' long-term follow-up information Up High TINCR expression was correlated with worse OS. – – [ 20 ] 24 cases of breast cancer tumor tissues and adjacent normal tissues Up High TINCR expression was correlated with worse prognosis.…”

Non-Coding RNAs: Regulating Disease Progression and Therapy Resistance in Hepatocellular Carcinoma

“…Upregulation of Terminal differentiation-induced ncRNA (TINCR), small nucleolar RNA host gene 5 (SNHG5), and HCC-associated lncRNA (HCAL) has been identified in human HCC, and potential mechanisms by which they promote HCC have been implicated by in vitro studies [49][50][51]. However, more in-depth in vivo studies are required to validate these findings.…”