The positive correlation of TIPRL with LC3 and CD133 contributes to cancer aggressiveness: potential biomarkers for early liver cancer

Abstract

Studies have reported dysregulation of TIPRL, LC3 and CD133 in liver cancer tissues. However, their respective relationships to liver cancer and roles as biomarkers for prognosis and diagnosis of liver cancer have never been studied. Here we report that the level of TIPRL is significantly correlated with levels of LC3 (Spearman r = 0.9) and CD133 (r = 0.7) in liver cancer tissues. We observed significant upregulations of TIPRL, LC3 and CD133 in hepatocellular carcinomas (HCCs) compared with adjacent normal tissues. Importantly, TIPRL, tested among additional variables, showed a significant impact on the prognosis of HCC patients. TIPRL knockdown significantly reduced expressions of LC3, CD133, stemness-related genes, as well as viability and stemness of liver cancer cell-lines, which were promoted by ectopic TIPRL expression. Either alone or as a combination, TIPRL, LC3 and CD133 showed significant values of area under the curve (AUC) and sensitivity/specificity in early liver cancer tissues. Furthermore, the statistical association and the diagnostic efficacies of TIPRL, LC3 and CD133 in HCC tissues were confirmed in a different IHC cohort. This data demonstrates that the complex involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness can together or individually serve as potential biomarkers for the early detection of liver cancer.

TIPRL, a Novel Tumor Suppressor, Suppresses Cell Migration, and Invasion Through Regulating AMPK/mTOR Signaling Pathway in Gastric Cancer

“…To date, the role of TIPRL in cancer has been documented only in liver and lung cancer (12,51,52). In hepatocellular carcinoma samples and cell lines, TIPRL is overexpressed and prevents TRAIL-induced apoptosis through inactivation of MKK7-JNK signaling (12), thereby representing a potential biomarker for early liver cancer (51). In addition, TIPRL overexpression is found to induce autophagy and accelerate growth through the eIF2α-ATF4 pathway in non-small cell lung cancer (52).…”

The Human TOR Signaling Regulator Is the Key Indicator of Liver Cancer Patients’ Overall Survival: TIPRL/LC3/CD133/CD44 as Potential Biomarkers for Early Liver Cancers

“…To further extend our previous reports that TIPRL contributes to the TRAIL resistance of HCCs [3] and to the aggressiveness of HCCs via positive regulation of LC3 and CD133 expression [8], we examined levels of all five variables, TIPRL, LC3, CD133, CD44, and CD46, previously reported to contribute to chemo-and radio-resistance in liver cancers. For this, we stained human liver disease tissues, including HCCs and iCCA, with the indicated antibodies and then determined the level of variables (Tables S1-S3) after performing global normalization using raw data obtained by confocal observation and the ZEN program (Figure 1A,C).…”

“…Regarding this pathway [6], we recently reported that TIPRL enhances cancer cell survival in metabolic and cellular stress via the induction of autophagic clearance [7]. TIPRL accelerates liver cancer aggressiveness via the upregulation of the microtubule-associated protein light chain 3 (LC3), an autophagy marker, and CD133 (Prominin-1) expression [8].…”

Autophagy, an accomplice or antagonist of drug resistance in HCC?

“…However, the combination of high Axl and low LC3 expression could significantly predict poorer prognosis for HCC patients who underwent hepatectomy in HCC 46 . Other data demonstrate that the complex involvement of TIPRL/LC3/CD133 in HCC aggressiveness can serve as potential biomarkers for early detection in a combined model or worked individually 47 . The above studies have demonstrated the potential of LC3 as a biomarker for early detection and early warning, but many challenges remain.…”