Transcriptomic profiling reveals hepatic stem-like gene signatures and interplay of miR-200c and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma

Abstract Background: SQSTM1/p62, as a selective autophagy receptor, regulates multiple signaling pathways participating in the initiation and progression of tumors. Since metastasis is still a main cause for intrahepatic cholangiocarcinoma (ICC)-associated mortality, this study aimed to explore the mechanism of p62 promoting progression of ICC.Methods: Western blotting and immunohistochemical analysis were conducted to detect the expression level of protein p62 in ICC tissues. Subsequently, loss of function experiments was applied to define the role of p62 in the progression of ICC in vitro and in vivo. Mitochondrial function and mitophagy was evaluated by measuring oxygen consumption rates (OCR) and immunofluorescence detection respectively.Results: Here we identified expression of p62 was significantly upregulated in ICC specimens compared to normal tissue. And we further illustrated that p62 expression was positively correlated with lymph-node metastasis and poor prognosis. Loss of function assays revealed that p62 not only promoted ICC cells proliferation, migration and invasive capacity in vitro, but also induced lung metastasis in xenograft mouse model. Mechanistically, high expression of p62 induced epithelial-mesenchymal transition (EMT) with upregulation of Snail1, Vimentin and down-regulation of E-Cadherin. Moreover, OCR assays and immunofluorescence cell staining demonstrated that the autophagy-dependent function of p62 may play a vital role in maintaining mitochondrial function of ICC by mitophagy.Conclusions: These data provide new evidence and feasible mechanism that abundant p62 expression promote ICC progression, suggesting a promising therapeutic target for anti-metastatic strategies in ICC patients.

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MiR-19b-3p facilitates the proliferation and epithelial-mesenchymal transition, and inhibits the apoptosis of intrahepatic cholangiocarcinoma by suppressing coiled-coil domain containing 6

Archives of Biochemistry and Biophysics ◽

10.1016/j.abb.2020.108367 ◽

2020 ◽

Vol 686 ◽

pp. 108367

Author(s):

Yi Tang ◽

Jianrong Yang ◽

Yonggang Wang ◽

Zhenyong Tang ◽

Sulai Liu ◽

...

Keyword(s):

Intrahepatic Cholangiocarcinoma ◽

Epithelial Mesenchymal Transition ◽

Coiled Coil ◽

Mesenchymal Transition ◽

Coiled Coil Domain

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MET overexpression as a hallmark of the epithelial-mesenchymal transition (EMT) phenotype in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3529 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3529-3529 ◽

Cited By ~ 1

Author(s):

Kanwal Pratap Singh Raghav ◽

Hesham M. Amin ◽

Wenting Wang ◽

Ganiraju C. Manyam ◽

Bradley Broom ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Overall Survival ◽

Protein Expression ◽

Protein Gene ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Gene Signatures ◽

Protein Levels ◽

Emt Markers

3529 Background: Epithelial-mesenchymal transition (EMT) has been identified as a dominant molecular subtype of colorectal cancer (CRC). This EMT phenotype as recognized by complex gene signatures is prognostic and associated with chemoresistance, but a biomarker for EMT suitable for clinical utilization has not yet been validated. The purpose of this study was to compare MET protein expression with protein/gene expression of EMT markers and to evaluate its impact on overall survival (OS). Methods: We performed an exploratory analysis of 139 untreated primary CRC samples using data from The Cancer Genome Atlas. Protein and gene expressions were measured using reverse-phase protein array (RPPA) and RNA-sequencing, respectively. MET high/overexpressed group was defined by protein level in the highest quartile. Mann-Whitney U-test and Spearman rank correlation was used to determine association between MET protein expression and protein/gene expression of EMT markers and EMT gene signature scores. Regression tree method and Kaplan-Meier estimates were used to assess overall survival (OS). Results: The MET protein distribution is right skewed, demonstrating a unique population of MET high expressing tumors (P < 0.01). Colon tumors had higher MET protein levels compared to rectal tumors (P < 0.01). MET overexpression was associated with decreased OS (HR 2.92; 95% CI: 1.45 - 5.92). MET protein expression correlated strongly with protein expressions of SLUG (transcription factor for EMT) (r = 0.6) and ERCC1 (a marker for oxaliplatin chemo-resistance) (r = 0.6) (P < 0.01). Higher MET protein levels were associated with higher gene expression of 28 EMT markers including AXL, VIM, ZEB1, ZEB2, FGF1, TGFB1I1 and MMP11 (P < 0.05). Higher MET protein levels were also associated with higher gene scores derived from three published EMT gene signatures (P < 0.05). MET protein expression did not correlate with MET gene expression (r = 0.16). Conclusions: Increased MET protein expression strongly correlates with a molecular EMT phenotype and poor survival in patients with CRC. MET protein expression may be used as a surrogate biomarker to represent and select for this unique molecular subset of CRC driven by EMT biology.

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