Lactotransferrin Downregulation Drives the Metastatic Progression in Clear Cell Renal Cell Carcinoma

Chiu, I‐Jen; Hsu, Yung‐Ho; Chang, Jeng-Shou; Yang, Jou-Chun; Chiu, Hung-Wen; Lin, Yuan

doi:10.3390/cancers12040847

Cited by 13 publications

(17 citation statements)

References 42 publications

(57 reference statements)

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“…We found that most ductal cells were derived from the normal pancreas (89.08%, 563/632), whereas only 68 ductal cells were derived from the adjacent normal tissue of the PASC sample (Figure 2 A and B). Notably, these cells were “entangled,” expressing antitumor genes such as LTF 24 , oncogenes such as CXCL6 25 , SAA1 26 , and S100A9 27 , and the inflammation gene CRP. Therefore, we consider this cell type a transitional cell type between healthy ductal and PASC cells.…”

Section: Resultsmentioning

confidence: 99%

Single-cell transcriptomics reveals heterogeneous progression and EGFR activation in pancreatic adenosquamous carcinoma

Zhao¹,

Li²,

Lyu³

et al. 2021

Int. J. Biol. Sci.

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Pancreatic adenosquamous carcinoma (PASC) — a rare pathological pancreatic cancer (PC) type — has a poor prognosis due to high malignancy. To examine the heterogeneity of PASC, we performed single-cell RNA sequencing (scRNA-seq) profiling with sample tissues from a healthy donor pancreas, an intraductal papillary mucinous neoplasm, and a patient with PASC. Of 9,887 individual cells, ten cell subpopulations were identified, including myeloid, immune, ductal, fibroblast, acinar, stellate, endothelial, and cancer cells. Cancer cells were divided into five clusters. Notably, cluster 1 exhibited stem-like phenotypes expressing UBE2C, ASPM, and TOP2A. We found that S100A2 is a potential biomarker for cancer cells. LGALS1, NPM1, RACK1, and PERP were upregulated from ductal to cancer cells. Furthermore, the copy number variations in ductal and cancer cells were greater than in the reference cells. The expression of EREG, FCGR2A, CCL4L2, and CTSC increased in myeloid cells from the normal pancreas to PASC. The gene sets expressed by cancer-associated fibroblasts were enriched in the immunosuppressive pathways. We demonstrate that EGFR-associated ligand-receptor pairs are activated in ductal-stromal cell communications. Hence, this study revealed the heterogeneous variations of ductal and stromal cells, defined cancer-associated signaling pathways, and deciphered intercellular interactions following PASC progression.

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Section: Resultsmentioning

confidence: 99%

Single-cell transcriptomics reveals heterogeneous progression and EGFR activation in pancreatic adenosquamous carcinoma

Zhao¹,

Li²,

Lyu³

et al. 2021

Int. J. Biol. Sci.

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“…In our previous report [ 24 ], we have demonstrated that a low-level LTF expression is associated with a high risk for cancer metastasis and poor prognosis in TCGA ccRCC patients. To ascertain a possible mechanism underlying the metastatic progression of ccRCC with LTF downregulation, here we firstly performed a computational simulation using the Gene Set Enrichment Analysis (GSEA) program.…”

Section: Resultsmentioning

confidence: 99%

“…Prior to the simulation, we generated two LTF-related gene sets derived from the TCGA ccRCC database and GSE36972 dataset. We generated one of LTF-related gene sets by performing LTF coexpression status that was ranked by Spearman’s correlation test with other somatic genes included in RNA sequencing experiment against primary tumors derived from TCGA ccRCC patients stratified as a low LTF-expression group in a Kaplan-Meier analysis [ 24 ] and recorded as lymph node metastasis ( Figure 1 A). On the other hand, we generated the other LTF gene set which was ranked by a log2 fold change of mRNA levels for all somatic genes in the LTF-overexpressing cells as compared to vector control cells in the GSE36972 dataset ( Figure 1 A).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, LTF appeared to suppress the cell growth of highly metastatic HT-29 colon cancer cells [ 23 ]. In our previous report, we have demonstrated that LTF downregulation forces the metastatic progression of ccRCC probably via activating several intracellular signaling cascades, e.g., the Akt/mTORC1 axis [ 24 ]. However, the comprehensive mechanism still needs to be further explored.…”

Section: Introductionmentioning

confidence: 99%

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Lactotransferrin Downregulation Serves as a Potential Predictor for the Therapeutic Effectiveness of mTOR Inhibitors in the Metastatic Clear Cell Renal Cell Carcinoma without PTEN Mutation

et al. 2021

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Approximately 30% of clear cell renal cell carcinoma (ccRCC) patients develop metastatic spread at the first diagnosis. Therefore, identifying a useful biomarker to predict ccRCC metastasis or therapeutic effectiveness in ccRCC patients is urgently needed. Previously, we demonstrated that lactotransferrin (LTF) downregulation enhanced the metastatic potential of ccRCC. Here, we show that LTF expression conversely associates with the mTORC1 activity as simulated by gene set enrichment analysis (GSEA). Moreover, Western blot analyses revealed that the LTF knockdown promoted, but the inclusion of recombinant human LTF protein suppressed, the phosphorylation of Akt/mTOR proteins in the detected ccRCC cells. Kaplan–Meier analyses demonstrated that the signature of combining an upregulated mTORC1 activity with a downregulated LTF expression referred to a worse overall and progression-free survival probabilities and associated with distant cancer metastasis in TCGA ccRCC patients. Furthermore, we found that the LTF-suppressed Akt/mTOR activation triggered an increased formation of autophagy in the highly metastatic ccRCC cells. The addition of autophagy inhibitor 3-methyadenine restored the LTF-suppressed cellular migration ability of highly metastatic ccRCC cells. Receiver operating characteristic (ROC) analyses showed that the expression of the LTF and MTORC1 gene set, not the autophagy gene set, could be the useful biomarkers to predict 5-year overall survival rate and cancer progression in ccRCC patients. Significantly, the signature of combining mTORC1 upregulation and LTF downregulation was shown as an independent prognostic factor in a multivariate analysis under the progression-free survival condition using the TCGA ccRCC database. Finally, the treatment with mTOR inhibitor rapamycin predominantly reduced the formation of autophagy and ultimately mitigated the cellular migration ability of ccRCC cells with LTF knockdown. Our findings suggest that LTF downregulation is a biomarker for guiding the use of mTOR inhibitors to combat metastatic ccRCC in the clinic.

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“…Apart from transgelin, 16 other proteins were identified as up-regulated in sunitinib non-responsive mccRCC. Of these, 10 proteins were previously reported to have associations with renal tumorigenesis: an elevated level of lactotransferrin (LTF) was reported in non-responsive mccRCC tumors; however, LTF was observed to block metastasis in ccRCC in other studies [ 50 , 51 ]. Clusterin was elevated in acquired resistance to sorafenib, another rTKI drug, in a mouse model [ 52 ] and it promoted the growth and invasion of RCC cells in vitro [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Transgelin Contributes to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment

et al. 2021

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Renal cell carcinoma (RCC) represents about 2–3% of all cancers with over 400,000 new cases per year. Sunitinib, a vascular endothelial growth factor tyrosine kinase receptor inhibitor, has been used mainly for first-line treatment of metastatic clear-cell RCC with good or intermediate prognosis. However, about one-third of metastatic RCC patients do not respond to sunitinib, leading to disease progression. Here, we aim to find and characterize proteins associated with poor sunitinib response in a pilot proteomics study. Sixteen RCC tumors from patients responding (8) vs. non-responding (8) to sunitinib 3 months after treatment initiation were analyzed using data-independent acquisition mass spectrometry, together with their adjacent non-cancerous tissues. Proteomics analysis quantified 1996 protein groups (FDR = 0.01) and revealed 27 proteins deregulated between tumors non-responding vs. responding to sunitinib, representing a pattern of deregulated proteins potentially contributing to sunitinib resistance. Gene set enrichment analysis showed an up-regulation of epithelial-to-mesenchymal transition with transgelin as one of the most significantly abundant proteins. Transgelin expression was silenced by CRISPR/Cas9 and RNA interference, and the cells with reduced transgelin level exhibited significantly slower proliferation. Our data indicate that transgelin is an essential protein supporting RCC cell proliferation, which could contribute to intrinsic sunitinib resistance.

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Lactotransferrin Downregulation Drives the Metastatic Progression in Clear Cell Renal Cell Carcinoma

Cited by 13 publications

References 42 publications

Single-cell transcriptomics reveals heterogeneous progression and EGFR activation in pancreatic adenosquamous carcinoma

Single-cell transcriptomics reveals heterogeneous progression and EGFR activation in pancreatic adenosquamous carcinoma

Lactotransferrin Downregulation Serves as a Potential Predictor for the Therapeutic Effectiveness of mTOR Inhibitors in the Metastatic Clear Cell Renal Cell Carcinoma without PTEN Mutation

Transgelin Contributes to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment

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