Significance of cytoplasmic expression of telomerase reverse transcriptase in patients with hepatocellular carcinoma undergoing liver resection

Nishi, Yusuke; Aoki, Taku; Shioiri, Takayuki; Sato, Shun; Matsumoto, Takatsugu; Sakai, Takayuki; Sakuraoka, Yuhki; Mori, Shiro; Iso, Yukihiro; Ishizuka, Mitsuru; Kubota, Keiichi

doi:10.3892/mco.2021.2406

Cited by 4 publications

(3 citation statements)

References 29 publications

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“…Cytoplasmic TERT has also been observed in clinical samples of HCC, and this is the predominant site of TERT expression. Cytoplasmic TERT expression is associated with poor tumor differentiation and oxidative stress-related DNA damage [15]. In addition to the telomere-lengthening function (canonical function) of nuclear TERT, cytoplasmic TERT has many secondary telomereindependent roles (noncanonical functions), such as interaction with signaling pathways, stress protection, and binding to and protection of mitochondrial DNA [9].…”

Section: Discussionmentioning

confidence: 99%

Complex phenotypic heterogeneity of combined hepatocellular-cholangiocarcinoma with a homogenous TERT promoter mutation

Ohni

2024

Am J Transl Res

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To clarify the mechanism underlying the development and poor prognosis of combined hepatocellularcholangiocarcinoma (cHCC-CCA), we characterized liver cancer driver mutations and poor prognostic markers in both the HCC and intrahepatic CCA (iCCA) components of a cHCC-CCA tumor. The telomerase reverse transcriptase (TERT) promoter mutation C228T was quantified by digital polymerase chain reaction using DNA from multiple microdissected cancer components of a single cHCC-CCA nodule. The protein expression of cancer-related markers, including TERT, was examined by serial thin-section immunohistochemistry and double-staining immunofluorescence. TERT promoter mutation and TERT protein expression were detected in all cancer components but not in noncancer regions. TERT promoter mutation frequencies were similar among components; those of TERT proteinpositive cancer cells were higher in iCCA and mixed components than in HCC. The frequencies of Ki67-and p53positive cells were similarly higher in iCCA and mixed components than in HCC. However, double-positive cells for the three proteins were unexpectedly rare; single-positive cells dominated, indicating phenotypic microheterogeneity in cancer cells within a component. Interestingly, HCC and CCA marker protein immunohistochemistry suggested dedifferentiation of HCC and transdifferentiation from HCC to iCCA in HCC and iCCA components, respectively. Such phenotypic intercomponent heterogeneity and intracomponent microheterogeneity were detected in a tumor nodule of cHCC-CCA uniformly carrying the early HCC driver mutation. Moreover, poor prognostic markers were randomly expressed without a regular pattern, consistent with the poor prognosis.

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Section: Discussionmentioning

confidence: 99%

Complex phenotypic heterogeneity of combined hepatocellular-cholangiocarcinoma with a homogenous TERT promoter mutation

Ohni

2024

Am J Transl Res

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“…However, in hepatocellular carcinomas, the marking was predominantly and exclusively cytoplasmic in 86/135 (64%), while only 3/135 (2.2%) were associated with nuclear marking. Furthermore, in these cases cytoplasmic labeling was associated with the presence of hepatitis B surface antigen ( p = 0.007) and poor cell differentiation ( p = 0.043) [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Nuclear and Cytoplasmic hTERT, Tumor-Infiltrating Lymphocytes, and Telomere Elongation Leukocytes Are Independent Factors in the Response to Neoadjuvant Treatment in HER2-Enriched Breast Cancer

et al. 2023

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HER2-enriched tumors are responsible for 20% of breast tumors and have high rates of immune infiltrates in the tumor stroma that respond favorably to neoadjuvant chemotherapy. In the context of tumors, telomeres control cell death and prevent tumor cells from replicating discontinuously, leading to their immortalization. This study aimed to evaluate the presence of tumor-infiltrating lymphocytes, hTERT expression, hTERT promoter mutation, and leukocyte telomere length in HER2-enriched breast tumors. A total of 103 cases were evaluated, 19 with pathologic complete response. The TILs percentage was above ≥10 in 44 cases (43%) and significantly present in patients ≥50 years of age. hTERT staining positivity was mostly nuclear, significantly present in the non-pCR group, and associated with a lower survival rate. Leukocyte telomeres were elongated for HER2-enriched tumors, and in multivariate analysis, shortening was associated with an increased risk of death. Overall, our results show that the nuclear and cytoplasmic presence of hTERT may indicate a worse prognosis and that leukocyte telomere elongation is a protective factor.

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“…We observed a strong cytoplasmic expression of TERT in the PGCC found in urine samples. Cytoplasmic expression of TERT was already observed in non-clear cell and clear cell hepatocellular carcinoma [ 34 , 35 ], cervical cancer [ 36 ], prostate cancer [ 37 ], and urothelial carcinoma [ 33 ], suggesting possible telomere-independent functions of TERT under conditions of environmental stress such as hypoxia and oxidative stress. As a matter of fact, PGCC are thought to be generated in response to stress conditions.…”

Section: Discussionmentioning

confidence: 99%

Polyploid Giant Cancer Cells Are Frequently Found in the Urine of Prostate Cancer Patients

Castillo¹,

Anract

Delongchamps

et al. 2023

Cancers

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Prostate cancer is the third cause of cancer-related deaths in men. Its early and reliable diagnosis is still a public health issue, generating many useless prostate biopsies. Prostate cancer cells detected in urine could be the target of a powerful test but they are considered too rare. By using an approach targeting rare cells, we have analyzed urine from 45 patients with prostate cancer and 43 healthy subjects under 50 y.o. We observed a relevant number of giant cells in patients with cancer. Giant cells, named Polyploid Giant Cancer Cells (PGCC), are thought to be involved in tumorigenesis and treatment resistance. We thus performed immune-morphological studies with cancer-related markers such as α-methylacyl-CoA racemase (AMACR), prostate-specific membrane antigen (PSMA), and telomerase reverse transcriptase (TERT) to understand if the giant cells we found are PGCC or other urinary cells. We found PGCC in the urine of 22 patients, including those with early-stage prostate cancer, and one healthy subject. Although these results are preliminary, they provide, for the first time, clinical evidence that prostate cancers release PGCC into the urine. They are expected to stimulate further studies aimed at understanding the role of urinary PGCC and their possible use as a diagnostic tool and therapeutic target.

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Significance of cytoplasmic expression of telomerase reverse transcriptase in patients with hepatocellular carcinoma undergoing liver resection

Cited by 4 publications

References 29 publications

Complex phenotypic heterogeneity of combined hepatocellular-cholangiocarcinoma with a homogenous TERT promoter mutation

Complex phenotypic heterogeneity of combined hepatocellular-cholangiocarcinoma with a homogenous TERT promoter mutation

Nuclear and Cytoplasmic hTERT, Tumor-Infiltrating Lymphocytes, and Telomere Elongation Leukocytes Are Independent Factors in the Response to Neoadjuvant Treatment in HER2-Enriched Breast Cancer

Polyploid Giant Cancer Cells Are Frequently Found in the Urine of Prostate Cancer Patients

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